ReactomeContentService4R: an R Interface for the Reactome Content Service
Overview
Reactome is a free, open-source, open access, curated and peer-reviewed knowledgebase of biomolecular pathways. Knowledge in Reactome is captured as instances of the classes with their associated attributes. The Reactome data model is comprised primarily of classes of Pathways, Reactions and PhysicalEntities (e.g. proteins, small molecules) that are organized in a hierarchical manner (Pathways contain Reactions, Reactions contain PhysicalEntities). Classes have attributes that hold properties of the represented class instances, such as names, identifiers, etc.
The ReactomeContentService4R package provides an
interface to query Reactome data from the Content Service.
This package allows you to query Reactome’s Content Service using many
of the same endpoints available on the website, but formats the returned
data in R Data Frames. For example, you can query all of the
participants/PhysicalEntities in a Reaction by providing its stable
identifier (‘R-HSA-123456’) to the
getParticipants("R-HSA-123456", retrieval="PhysicalEntities")
method in the package. This will return an R Data Frame that will hold
the same attributes as the Content Service query
curl -X GET "https://reactome.org/ContentService/data/participants/R-HSA-123456" -H "accept: application/json".
Similar functionality exists for a number of other Reactome Content Service endpoints, which is outlined further below in this document. You can retrieve specific instances, or all instances within a specific Class (eg: Pathway or Complex); Generate mappings, such as PhysicalEntity-to-Events (ie. Proteins to Reactions) mappings, or non-Reactome identifiers (such as UniProt) to Events/PhysicalEntities (for example, Reactome Proteins containing UniProt identifiers) mappings; Export or view Reactome’s Pathway/Reaction diagrams, and much more!
Installation
Install from Bioconductor:
if (!requireNamespace("BiocManager")) {
install.packages("BiocManager")
}
BiocManager::install("ReactomeContentService4R")## Connecting...welcome to Reactome v90!Instance fetching
Fetch by Class
To retrieve instances of one Class, you can use
getSchemaClass. This function would first show how many
instances belong to the specified Class in the Reactome Database, and
return 1000 instances by default. If you want to retrieve all instances
of one Class, specify all = TRUE.
Argument species could be specified here but only for
Event or subclasses with species attribute under PhysicalEntity
(i.e. Complex, EntitySet, etc). Some attributes are also retrieved and
thus they can be used to filter. For example, to fetch all human
pathways, and then select those in disease:
# Fetch all Human Pathways
pathways <- getSchemaClass(class = "Pathway", species = "human", all = TRUE)## Total 2742 entries of Pathway with species Homo sapiens, retrieving 2742 of them...## | | | 0%## dbId displayName stId
## <int> <char> <char>
## 1: 15869 Metabolism of nucleotides R-HSA-15869
## 2: 68616 Assembly of the ORC complex at the origin of replication R-HSA-68616
## 3: 68689 CDC6 association with the ORC:origin complex R-HSA-68689
## 4: 68867 Assembly of the pre-replicative complex R-HSA-68867
## 5: 68875 Mitotic Prophase R-HSA-68875
## stIdVersion isInDisease isInferred
## <char> <lgcl> <lgcl>
## 1: R-HSA-15869.7 FALSE FALSE
## 2: R-HSA-68616.6 FALSE FALSE
## 3: R-HSA-68689.6 FALSE FALSE
## 4: R-HSA-68867.10 FALSE FALSE
## 5: R-HSA-68875.7 FALSE FALSE
## name releaseDate
## <list> <char>
## 1: Metabolism of nucleotides,Nucleotide metabolism 2004-07-06
## 2: Assembly of the ORC complex at the origin of replication 2004-07-06
## 3: CDC6 association with the ORC:origin complex 2004-07-06
## 4: Assembly of the pre-replicative complex 2004-07-06
## 5: Mitotic Prophase 2004-07-06
## speciesName hasDiagram hasEHLD lastUpdatedDate schemaClass className
## <char> <lgcl> <lgcl> <char> <char> <char>
## 1: Homo sapiens TRUE TRUE 2022-06-09 Pathway Pathway
## 2: Homo sapiens FALSE FALSE 2021-12-08 Pathway Pathway
## 3: Homo sapiens FALSE FALSE 2021-12-08 Pathway Pathway
## 4: Homo sapiens FALSE FALSE 2021-12-08 Pathway Pathway
## 5: Homo sapiens TRUE FALSE 2023-03-29 Pathway Pathway
## releaseStatus doi
## <char> <char>
## 1: <NA> <NA>
## 2: <NA> 10.3180/R-HSA-68616.3
## 3: <NA> <NA>
## 4: <NA> 10.3180/R-HSA-68867.7
## 5: <NA> <NA>
## definition
## <char>
## 1: <NA>
## 2: <NA>
## 3: <NA>
## 4: <NA>
## 5: The initial stage of mitosis in which the chromosomes are condensed but are not yet attached to a mitotic spindle.# Filter Disease Pathways from results
disease.pathways <- pathways[pathways$isInDisease == TRUE, ]
head(disease.pathways, 5)## dbId displayName stId stIdVersion
## <int> <char> <char> <char>
## 1: 162585 Uncoating of the HIV Virion R-HSA-162585 R-HSA-162585.3
## 2: 162587 HIV Life Cycle R-HSA-162587 R-HSA-162587.5
## 3: 162588 Budding and maturation of HIV virion R-HSA-162588 R-HSA-162588.4
## 4: 162589 Reverse Transcription of HIV RNA R-HSA-162589 R-HSA-162589.3
## 5: 162592 Integration of provirus R-HSA-162592 R-HSA-162592.5
## isInDisease isInferred name releaseDate
## <lgcl> <lgcl> <list> <char>
## 1: TRUE FALSE Uncoating of the HIV Virion 2006-11-14
## 2: TRUE FALSE HIV Life Cycle 2006-01-23
## 3: TRUE FALSE Budding and maturation of HIV virion 2013-06-11
## 4: TRUE FALSE Reverse Transcription of HIV RNA 2006-11-14
## 5: TRUE FALSE Integration of provirus 2006-11-14
## speciesName hasDiagram hasEHLD lastUpdatedDate schemaClass className
## <char> <lgcl> <lgcl> <char> <char> <char>
## 1: Homo sapiens FALSE FALSE 2013-06-30 Pathway Pathway
## 2: Homo sapiens TRUE FALSE 2020-09-24 Pathway Pathway
## 3: Homo sapiens FALSE FALSE 2020-09-24 Pathway Pathway
## 4: Homo sapiens FALSE FALSE 2020-09-24 Pathway Pathway
## 5: Homo sapiens FALSE FALSE 2018-06-13 Pathway Pathway
## releaseStatus doi definition
## <char> <char> <char>
## 1: <NA> <NA> <NA>
## 2: <NA> 10.3180/REACT_6256.3 <NA>
## 3: <NA> 10.3180/REACT_6359.6 <NA>
## 4: <NA> <NA> <NA>
## 5: <NA> <NA> <NA>Fetch by identifier
Now that we have got all those disease pathways, we can look into
what disease(s) associated with a pathway of your interest. The
query function could fetch all attributes
of an instance with any Class by its database id or stable id.
It also lists any second level relationships regarding regulations and
catalysts. As an example, to retrieve one of the human disease pathway
“Activated point mutants of FGFR2” with identifier R-HSA-2033519:
# Fetch the Reactome object with all attributes using a given id
hsa.2033519 <- query(id = "R-HSA-2033519")
str(hsa.2033519, max.level = 1)## List of 25
## $ dbId : int 2033519
## $ displayName : chr "Activated point mutants of FGFR2"
## $ stId : chr "R-HSA-2033519"
## $ stIdVersion : chr "R-HSA-2033519.2"
## $ created :List of 5
## $ modified :List of 5
## $ isInDisease : logi TRUE
## $ isInferred : logi FALSE
## $ name : chr "Activated point mutants of FGFR2"
## $ releaseDate : chr "2012-06-12"
## $ speciesName : chr "Homo sapiens"
## $ authored :'data.frame': 1 obs. of 5 variables:
## $ compartment :'data.frame': 3 obs. of 9 variables:
## $ disease :'data.frame': 2 obs. of 10 variables:
## $ edited :'data.frame': 1 obs. of 5 variables:
## $ literatureReference:'data.frame': 17 obs. of 11 variables:
## $ reviewed :'data.frame': 1 obs. of 5 variables:
## $ species :'data.frame': 1 obs. of 8 variables:
## $ summation :'data.frame': 1 obs. of 5 variables:
## $ reviewStatus :List of 6
## $ hasDiagram : logi FALSE
## $ hasEHLD : logi FALSE
## $ hasEvent :'data.frame': 10 obs. of 15 variables:
## $ schemaClass : chr "Pathway"
## $ className : chr "Pathway"The schemaClass of R-HSA-2033519 is Pathway
since we get this id by getSchemaClass for Pathway.
Likewise, we can always access what Class an instance belongs to using
query.
Here we look into the disease slot to find disease associated with this Pathway:
## dbId displayName databaseName
## 1 1500689 cancer DOID
## 2 2032940 bone development disease DOID
## definition
## 1 A disease of cellular proliferation that is malignant and primary, characterized by uncontrolled cellular proliferation, local cell invasion and metastasis.
## 2 A bone disease that results_in abnormal growth and development located_in bone or located_in cartilage.
## identifier name
## 1 162 cancer
## 2 0080006 bone development disease
## synonym
## 1 malignant tumor, malignant neoplasm, primary cancer
## 2 NULL
## url className
## 1 https://www.ebi.ac.uk/ols/ontologies/doid/terms?obo_id=DOID:162 Disease
## 2 https://www.ebi.ac.uk/ols/ontologies/doid/terms?obo_id=DOID:0080006 Disease
## schemaClass
## 1 Disease
## 2 DiseaseSearch for name
We can see that the pathway “Activated point mutants of FGFR2” is
related to two disease: “bone development disease” and “cancer”. If you
want to know more about bone development disease, you may try to use the
query function again with its dbId to obtain more details.
However, you would just get a Reactome Disease object that doesn’t
include any other biological insights in Reactome. For now, you can use
searchQuery function which fetches all instances associated
with a term:
# Search for a human disease name
bdd.search <- searchQuery(query = "bone development disease", species = "human")## Searching for term 'bone development disease'... species:'Homo sapiens'## entries
## 1 8941326, 1643685, 5663205, 9830369, 9831926, 5655302, 1226099, 5655253, 5655332, 5655291, R-HSA-8941326, R-HSA-1643685, R-HSA-5663205, R-HSA-9830369, R-HSA-9831926, R-HSA-5655302, R-HSA-1226099, R-HSA-5655253, R-HSA-5655332, R-HSA-5655291, R-HSA-8941326, R-HSA-1643685, R-HSA-5663205, R-HSA-9830369, R-HSA-9831926, R-HSA-5655302, R-HSA-1226099, R-HSA-5655253, R-HSA-5655332, R-HSA-5655291, RUNX2 regulates <span class="highlighting" >bone</span> <span class="highlighting" >development</span>, <span class="highlighting" >Disease</span>, Infectious <span class="highlighting" >disease</span>, Kidney <span class="highlighting" >development</span>, Nephron <span class="highlighting" >development</span>, Signaling by FGFR1 in <span class="highlighting" >disease</span>, Signaling by FGFR in <span class="highlighting" >disease</span>, Signaling by FGFR2 in <span class="highlighting" >disease</span>, Signaling by FGFR3 in <span class="highlighting" >disease</span>, Signaling by FGFR4 in <span class="highlighting" >disease</span>, Pathway, TopLevelPathway, Pathway, Pathway, Pathway, Pathway, Pathway, Pathway, Pathway, Pathway, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, RUNX2 is required for the <span class="highlighting" >development</span> of both intramembraneous and endochondral bones through regulation of osteoblast differentiation and chondrocyte maturation, respectively. In its absence, intramembraneous ossification is blocked while endochondral ossification is arrested at the cartilaginous stage (Otto et al. 1997, Komori et al. 1997). In mice and humans, RUNX2 haploinsufficiency causes Cleidocranial dysplasia, a generalized <span class="highlighting" >bone</span> disorder (Otto et al. 1997, Lee et al. 1997).<br>RUNX2 stimulates transcription of most of the genes constituting the <span class="highlighting" >bone</span> extracellular matrix and of BGLAP gene, which encodes Osteocalcin, a <span class="highlighting" >bone</span>-derived hormone controlling glucose metabolism, male fertility and cognition (Ducy et al. 1997).<br>RUNX2 promotes chondrocyte maturation by stimulating transcription of the IHH gene, encoding Indian hedgehog (Takeda et al. 2001, Yoshida et al. 2004).<br>In response to BMP2 signaling, RUNX2 forms a complex with SMAD1:SMAD4 heterotrimer in the nucleus and stimulates transcription of SMAD6 (Wang et al. 2007).<br>RBM14, a negative regulator of RUNX2 transcriptional activity, is frequently overexpressed in osteosarcoma (Li et al. 2009)., Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human <span class="highlighting" >disease</span> pathways have three mechanistic causes: the inclusion of microbially-expressed proteins, altered functions of human proteins, or changed expression levels of otherwise functionally normal human proteins.<p>The first group encompasses the infectious diseases such as influenza, tuberculosis and HIV infection. The second group involves human proteins modified either by a mutation or by an abnormal post-translational event that produces an aberrant protein with a novel function. Examples include somatic mutations of EGFR and FGFR (epidermal and fibroblast growth factor receptor) genes, which encode constitutively active receptors that signal even in the absence of their ligands, or the somatic mutation of IDH1 (isocitrate dehydrogenase 1) that leads to an enzyme active on 2-oxoglutarate rather than isocitrate, or the abnormal protein aggregations of amyloidosis which lead to diseases such as Alzheimer's.<p>Infectious diseases are represented in Reactome as microbial-human protein interactions and the consequent events. The existence of variant proteins and their association with <span class="highlighting" >disease</span>-specific biological processes is represented by inclusion of the modified protein in a new or variant reaction, an extension to the 'normal' pathway. Diseases which result from proteins performing their normal functions but at abnormal rates can also be captured, though less directly. Many mutant alleles encode proteins that retain their normal functions but have abnormal stabilities or catalytic efficiencies, leading to normal reactions that proceed to abnormal extents. The phenotypes of such diseases can be revealed when pathway annotations are combined with expression or rate data from other sources.<br><br>Depending on the biological pathway/process immediately affected by <span class="highlighting" >disease</span>-causing gene variants, non-infectious diseases in Reactome are organized into diseases of signal transduction by growth factore receptors and second messengers, diseases of mitotic cell cycle, diseases of cellular response to stress, diseases of programmed cell death, diseases of DNA repair, disorders of transmembrane transporters, diseases of metabolism, diseases of immune system, diseases of neuronal system, disorders of developmental biology, disorders of extracellular matrix organization, and diseases of hemostatis., Infectious diseases are ones due to the presence of pathogenic microbial agents in human host cells. Processes annotated in this category include bacterial, viral and parasitic infection pathways.<br><br>Bacterial infection pathways currently include some metabolic processes mediated by intracellular Mycobacterium tuberculosis, the actions of clostridial, anthrax, and diphtheria toxins, and the entry of Listeria monocytogenes into human cells.<br><br>Viral infection pathways currently include the life cycles of SARS-CoV viruses, influenza virus, HIV (human immunodeficiency virus), and human cytomegalovirus (HCMV).<br><br>Parasitic infection pathways currently include Leishmania infection-related pathways.<br><br>Fungal infection pathways and prion diseases have not been annotated., Kidney <span class="highlighting" >development</span> begins at embryonic day 8.5 (E8.5) in mouse embryos, a time after gastrulation and formation of the intermediate mesoderm (reviewed in Marcotte et al. 2014, Smyth 2021, Schnell et al. 2022). Renal progenitors are specified within the intermediate mesoderm in the region between the 6th and 8th somites. The nephric duct then begins to form by mesenchymal to epithelial transitions of the renal progenitors and grows caudally to fuse with the bladder and urethra primordium (cloaca). The nephric duct induces the formation of mesonephric tubules in the adjacent nephric cord which form the mesonephros, an embryonic kidney in mammals that regresses and is supplanted by the metanephros. (In anamniotes such as frogs and fish, the mesonephros is the adult kidney and no metanephros forms.) <br>In mammals, the metanephros is initiated as the caudal region of the nephric cord forms metanephric mesenchyme which then interacts with the nephric duct to induce formation of the ureteric bud, the progenitor of the ureter. Branching of the ureteric bud forms ureter tips which induce nephron formation in the surrounding metanephric mesenchyme (reviewed in El-Dahr et al. 2008, O'Brien and McMahon 2014, Desgrange and Cereghini 2015, Chambers and Wingert 2020, Schnell et al. 2022). <br>Induction of kidney <span class="highlighting" >development</span> in the intermediate mesoderm occurs by incompletely characterized signals from the adjacent ectoderm and lateral plate mesoderm. Notably, BMP activity from the lateral plate mesoderm can induce expression of the renal markers Pax2 and Lhx1.<br>Foxc1 and Foxc2 expressed in the paraxial mesoderm repress Lhx1 and prevent over-expansion of the intermediate mesoderm (Wilm et al. 2004). Conversely, Nodal signaling maintains Pax2 expression and prevents over-expansion of the paraxial mesoderm (Fleming et al. 2013). The rostral-caudal position of renal <span class="highlighting" >development</span> appears to specified by the rostral-caudal gradient of retinoic acid acting through HoxB4 (Preger-Ben Noon et al. 2009) and limited caudally by HoxA6. <br>The combined expression of Pax2, Pax8, Lhx1, and Gata3 is the earliest observed marker of the renal lineage and these transcription factors, together with Emx2, form a self-reinforcing module that drives formation of the nephric duct. Nephronectin (Npnt) from the nephric duct interacts with integrin alpha8/beta1 (Itga8) on the metanephric mesenchyme and Ret located on the nephric duct interacts with Gdnf secreted by the metanephric mesenchyme to regulate formation and branching of the ureteric bud (reviewed in Marcotte et al. 2014). Signals from the tips of the ureteric bud then induce epithelialization of the metanephric mesenchyme and formation of nephrons, the basic filtration units of the kidney comprising the glomerulus, the proximal tubule, the loop of Henle, and the distal tubule (reviewed in Desgrange and Cereghini 2015). Canonical Wnt signaling from the ureteric bud appears to be the main inductive event: Wnt9b activates Wnt4 expression to epithelialize mesenchymal pre-tubular aggregates and Wnt9b also supports expression of Six2 to maintain a nephron progenitor pool in the cap mesenchyme.<br>Congenital anomalies of the kidney and urinary tract (CAKUT) comprise about 30% of antnatal congenital abnormalities and cause the majority of chronic kidney <span class="highlighting" >disease</span> in children (reviewed in Costigan and Rosenblum 2022). Knowledge gained from studying kidney <span class="highlighting" >development</span> is being used to generate kidney organoids in vitro with a goal of producing transplantable kidney tissue (reviewed in Kalejaiye et al. 2022, Safi et al. 2022, Trush and Takasato 2022, Shi et al. 2023)., A nephron of an amniote such as mouse or human comprises the glomerulus where small molecules are filtered out of the blood, the proximal tubule and the loop of Henle where small molecules are selectively reabsorbed, the thick ascending limb, the macula densa, the distal convoluted tubule, the connecting tubule, and the collecting duct which drains into the ureter.<br>Initiation of nephron <span class="highlighting" >development</span> occurs at the termini of the branches of the ureteric bud where cells of the ureteric bud interact with cells of the metanephric mesenchyme. Rather than differentiating in place, analysis of cellular migration indicates that progenitors are recruited from the mesenchyme to the developing epithelial elements of the nephron (Lindstrom et al. 2018). The transcriptional program that operates during human nephrogenesis has been mapped in extraordinary detail (Lindstrom et al. 2021). WNT9B secreted by the ureteric bud induces a subset of renal progenitor cells to aggregate and express WNT4, which causes the pre-tubular aggregates to further undergo a mesenchymal to epithelial transition to form renal vesicles (inferred from mouse embryos in Park et al. 2007, reviewed in El-Dahr et al. 2008, Costantini and Kopan 2010, Desgrange and Cereghini 2015). A subset of renal progenitor cells express SIX2 and respond to WNT9B by proliferating to maintain a renewing population of renal progenitors. The reason for the difference in responses may be the local concentration of WNT9B (inferred from mouse embryos in Ramalingam et al. 2018) or the presence of the transcription factor SIX2 (inferred from mouse embryos in Karner et al. 2011).<br>The renal vesicle becomes polarized early. The distal region contains a gene regulatory network containing LHX1, POU3F3 (BRN1), DLL1, and JAG1. LHX1 is required for proximo-distal differentiation (inferred from mouse embryos in Kobayashi et al. 2005) and POU3F3 participates in elongation of the loop of Henle and formation of the distal convoluted tubule (inferred from mouse embryos in Nakai et al. 2003). The proximal region of the renal vesicle expresses WT1, which directly represses PAX2 to enable formation of podocytes (inferred from mouse homologs in Ryan et al. 1995). The renal vesicle develops into the comma-shaped body in which HNF1B in the distal region activates NOTCH pathway components DLL1, JAG1, and LFNG (inferred from mouse embryos in Heliot et al. 2013). The comma-shaped body in turn develops into the S-shaped body in which HNF1B activates IRX1 and IRX2 in the intermediate region (inferred from mouse embryos in Heliot et al. 2013). Podocytes, the proximal tubule, the intermediate tubule, and the distal tubule then differentiate., The FGFR1 gene has been shown to be subject to activating mutations, chromosomal rearrangements and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007; Wesche, 2011; Greulich and Pollock, 2011). <br><br><br>Activating mutation P252R in FGFR1 is associated with the <span class="highlighting" >development</span> of Pfeiffer syndrome, characterized by craniosynostosis (premature fusion of several sutures in the skull) and broadened thumbs and toes (Muenke, 1994; reviewed in Cunningham, 2007). This residue falls in a highly conserved Pro-Ser dipeptide between the second and third Ig domains of the extracellular region of the receptor. The mutation is thought to increase the number of hydrogen bonds formed with the ligand and to thereby increase ligand-binding affinity (Ibrahimi, 2004a). Unlike other FGF receptors, few activating point mutations in the FGFR1 coding sequence have been identified in cancer. Point mutations in the Ig II-III linker analagous to the P252R Pfeiffer syndrome mutation have been identified in lung cancer and melanoma (Ruhe, 2007; Davies, 2005), and two kinase-domain mutations in FGFR1 have been identified in glioblastoma (Rand, 2005, Network TCGA, 2008).<br><br>In contrast, FGFR1 is a target of chromosomal rearrangements in a number of cancers. FGFR1 has been shown to be recurrently translocated in the 8p11 myeloproliferative syndrome (EMS), a pre-leukemic condition also known as stem cell leukemia/lymphoma (SCLL) that rapidly progresses to leukemia. This translocation fuses the kinase domain of FGFR1 with the dimerization domain of one of 10 identified fusion partners, resulting in the constitutive dimerization and activation of the kinase (reviewed in Jackson, 2010). <br><br>Amplification of the FGFR1 gene has been implicated as a oncogenic factor in a range of cancers, including breast, ovarian, bladder, lung, oral squamous carcinomas, and rhabdomyosarcoma (reviewed in Turner and Grose, 2010; Wesche, 2011; Greulich and Pollock, 2011), although there are other candidate genes in the amplified region and the definitive role of FGFR1 has not been fully established.<br>More recently, FGFR1 fusion proteins have been identified in a number of cancers; these are thought to undergo constitutive ligand-independent dimerization and activation based on dimerization motifs found in the fusion partners (reviewed in Parker, 2014)., A number of skeletal and developmental diseases have been shown to arise as a result of mutations in the FGFR1, 2 and 3 genes. These include dwarfism syndromes (achondroplasia, hypochondroplasia and the neonatal lethal disorders thanatophoric dysplasia I and II), as well as craniosynostosis disorders such as Pfeiffer, Apert, Crouzon, Jackson-Weiss and Muenke syndromes (reviewed in Webster and Donoghue 1997; Burke, 1998, Cunningham, 2007; Harada, 2009). These mutations fall into four general regions of the receptor: a) the immunoglobulin (Ig)-like domain II-III linker region, b) the alternatively spliced second half of the Ig III domain, c) the transmembrane domain and d) the tyrosine kinase domain (reviewed in Webster and Donoghue, 1997). With the exception of mutations in class b), which affect only the relevant splice variant, these mutations may be present in either the 'b' or 'c' isoforms. These activating mutations affect FGFR function by altering or expanding the ligand-binding range of the receptors (see for instance Ibrahimi, 2004a), by promoting ligand-independent dimerization (for instance, Galvin,1996; Neilson and Friesel, 1996; d'Avis,1998) or by increasing the activity of the kinase domain (for instance, Webster, 1996; Naski, 1996; Tavormina, 1999; Bellus, 2000). Thus, a number of the point mutations found in FGFR receptors alter their activity without altering their intrinsic kinase activity. Many of the mutations that promote constitutive dimerization do so by creating or removing cysteine residues; the presence of an unpaired cysteine in the receptor is believed to promote dimerization through the formation of intramolecular disulphide bonds (Galvin, 1996; Robertson, 1998). Paralogous mutations at equivalent positions have been identified in more than one FGF receptor, sometimes giving rise to different diseases. For instance, mutation of the highly conserved FGFR2 Ser252-Pro253 dipeptide in the region between the second and third Ig domain is responsible for virtually all cases of Apert Syndrome (Wilkie, 1995), while paralogous mutations in FGFR1 (S252R) and FGFR3 (P250R) are associated with Pfeiffer and Crouzon syndromes, respectively (Bellus, 1996). FGFR4 is unique in that mutations of this gene are not known to be associated with any developmental disorders.<br><br>Recently, many of the same activating mutations in the FGFR genes that have been characterized in skeletal and developmental disorders have begun to be identified in a range of cancers (reviewed in Turner and Gross, 2010; Greulich and Pollock, 2011; Wesche, 2011). The best established link between a somatic mutation of an FGFR and the <span class="highlighting" >development</span> of cancer is in the case of FGFR3, where 50% of bladder cancers have mutations in the FGFR3 coding sequence. Of these mutations, which largely match the activating mutations seen in thanatophoric dysplasias, over half occur at a single residue (S249C) (Cappellen, 1999; van Rhijn, 2002). Activating mutations have also been identified in the coding sequences of FGFR1, 2 and 4 (for review, see Wesche, 2011)<br><br>In addition to activating point mutations, the FGFR1, 2 and 3 genes are subject to misregulation in cancer through gene amplification and translocation events, which are thought to lead to overexpression and ligand-independent dimerization (Weiss, 2010; Turner, 2010; Kunii, 2008; Takeda, 2007; Chesi, 1997; Avet-Loiseau, 1998; Ronchetti, 2001). It is important to note, however, that in each of these cases, the amplification or translocation involve large genomic regions encompassing additional genes, and the definitive roles of the FGFR genes in promoting oncogenesis has not been totally established. In the case of FGFR1, translocation events also give rise to FGFR1 fusion proteins that contain the intracellular kinase domain of the receptor fused to a dimerization domain from the partner gene. These fusions, which are expressed in a pre-leukemic myeloproliferative syndrome, dimerize constitutively based on the dimerization domain provided by the fusion partner and are constitutively active (reviewed in Jackson, 2010).<br><br>, The FGFR2 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically. Activating FGFR2 mutations in the germline give rise to a range of craniosynostotic conditions including Pfeiffer, Apert, Jackson-Weiss, Crouzon and Beare-Stevensen Cutis Gyrata syndromes. These autosomal dominant skeletal disorders are characterized by premature fusion of several sutures in the skull, and in some cases also involve syndactyly (abnormal <span class="highlighting" >bone</span> fusions in the hands and feet) (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007). <br><br>Activating FGFR2 mutations arising somatically have been linked to the <span class="highlighting" >development</span> of gastric and endometrial cancers (reviewed in Greulich and Pollock, 2011; Wesche, 2011). Many of these mutations are similar or identical to those that contribute to the autosomal disorders described above. Notably, loss-of-function mutations in FGFR2 have also been recently described in melanoma (Gartside, 2009). FGFR2 may also contribute to tumorigenesis through overexpression, as FGFR2 has been identified as a target of gene amplification in gastric and breast cancers (Kunii, 2008; Takeda, 2007)., The FGFR3 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically. <br><br>Activating mutations in FGFR3 are associated with the <span class="highlighting" >development</span> of a range of skeletal dysplasias that result in dwarfism (reviewed in Webster and Donoghue, 1997; Burke et al, 1998; Harada et al, 2009). The most common form of human dwarfism is achondroplasia (ACH), which is caused by mutations G380R and G375C in the transmembrane domain of FGFR3 that are thought to promote ligand-independent dimerization (Rousseau et al, 1994; Shiang et al, 1994; Bellus et al, 1995a) Hypochondroplasia (HCH) is a milder form dwarfism that is the result of mutations in the tyrosine kinase domain of FGFR3 (Bellus et al, 1995b). Two neonatal lethal conditions, thanatophoric dysplasia type I and II (TDI and TDII) are also the result of mutations in FGFR3; TDI arises from a range of mutations that either result in the formation of unpaired cysteine residues in the extracellular region that promote aberrant ligand-independent dimerization or by mutations that introduce stop codons (Rousseau et al, 1995; Rousseau et al, 1996, D'Avis et al,1998). A single mutation, K650E in the second tyrosine kinase domain of FGFR3 is responsible for all identified cases of TDII (Tavormina et al, 1995a, b). Other missense mutations at the same K650 residue give rise to Severe Achondroplasia with Developmental Disorders and Acanthosis Nigricans (SADDAN) syndrome (Tavormina et al, 1999; Bellus et al, 1999). The severity of the phenotype arising from many of the activating FGFR3 mutations has recently been shown to correlate with the extent to which the mutations activate the receptor (Naski et al, 1996; Bellus et al, 2000) <br><br>In addition to mutations that cause dwarfism syndromes, a Pro250Arg mutation in the conserved dipeptide between the IgII and IgIII domains has been identified in an atypical craniosynostosis condition (Bellus et al, 1996; Reardon et al, 1997). This mutation, which is paralogous to mutations seen in FGFR1 and 2 in Pfeiffer and Apert Syndrome, respectively, results in an increase in ligand-binding affinity for the receptor (Ibrahimi et al, 2004b).<br><br><br>Of all the FGF receptors, FGFR3 has perhaps the best established link to the <span class="highlighting" >development</span> in cancer. 50% of bladder cancers have somatic mutations in the coding sequence of FGFR3; of these, more than half occur in the extracellular region at a single position (S249C) (Cappellen et al, 1999; Naski et al, 1996; di Martino et al, 2009, Sibley et al, 2001). Activating mutations are also seen in the juxta- and trans-membrane domains, as well as in the kinase domain (reviewed in Weshe et al, 2011). As is the case for the other receptors, many of the activating mutations that are seen in FGFR3-related cancers mimic the germline FGFR3 mutations that give rise to autosomal skeletal disorders and include both ligand-dependent and independent mechanisms (reviewed in Webster and Donoghue, 1997; Burke et al, 1998). In addition to activating mutations, the FGFR3 gene is subject to a translocation event in 15% of multiple myelomas (Avet-Loiseau et al, 1998; Chesi et al, 1997). This chromosomal rearrangement puts the FGFR3 gene under the control of the highly active IGH promoter and promotes overexpression and constitutive activation of FGFR3. In a small proportion of multiple myelomas, the translocation event is accompanied by activating mutations in the FGFR3 coding sequence (Chesi et al, 1997).<br><br>More recently, a number of fusion proteins of FGFR3 have been identified in various cancers (Singh et al, 2012; Williams et al, 2013; Parker et al, 2013; Wu et al, 2013; Wang et al, 2014; Yuan et al, 2014; reviewed in Parker et al, 2014). The most common fusion protein is TACC3, a coiled coil protein involved in mitotic spindle assembly. FGFR3 fusion proteins are constitutively active and appear to contribute to proliferation and tumorigenesis through activation of the ERK and AKT signaling pathways (reviewed in Parker et al, 2014)., FGFR4 is perhaps the least well studied of the FGF receptors, and unlike the case for the other FGFR genes, mutations in FGFR4 are not known to be associated with any developmental disorders. Recently, however, somatically arising mutations in the FGFR4 coding sequence have begun to be identified in some cancers. 8% of rhabdomyosarcomas have activating mutations in the kinase domain of FGFR4. Two of these mutations - N535K (paralogous to the FGFR2 N550K allele found in endometrial cancers) and V550E - have been shown to support the oncogenic transformation of NIH 3T3 cells (Taylor, 2009). An FGFR4 Y367C mutation has also been identified in breast cancers (Ruhe, 2007; Roidl, 2010); mutations of paralogous residues in FGFR2 and FGFR3 are associated with both skeletal dysplasias and the <span class="highlighting" >development</span> of diverse cancers (Pollock, 2007; Ruhe, 2007; Rousseau, 1996; Chesi, 1997, 2001).<br><br><br>Finally, a SNP at position 388 of FGFR4 is associated with aggressive <span class="highlighting" >disease</span> <span class="highlighting" >development</span>. Expression of the G388R allele in breast, colorectal and prostate cancers is correlated with rapid progression times and increased rates of recurrence and metastasis (Bange, 2002; Spinola, 2005; Wang, 2004)., FALSE, TRUE, TRUE, FALSE, FALSE, TRUE, TRUE, TRUE, TRUE, TRUE
## 2 9832208, 9832183, 9833362, 9832230, 9832331, 9832340, 9832209, 9832187, 9832687, 9832205, R-HSA-9832208, R-HSA-9832183, R-HSA-9833362, R-HSA-9832230, R-HSA-9832331, R-HSA-9832340, R-HSA-9832209, R-HSA-9832187, R-HSA-9832687, R-HSA-9832205, R-HSA-9832208, R-HSA-9832183, R-HSA-9833362, R-HSA-9832230, R-HSA-9832331, R-HSA-9832340, R-HSA-9832209, R-HSA-9832187, R-HSA-9832687, R-HSA-9832205, Expression of IRX2 during nephron <span class="highlighting" >development</span>, Expression of IRX1 during nephron <span class="highlighting" >development</span>, Expression of WNT9B during nephron <span class="highlighting" >development</span>, Expression of POU3F3 during nephron <span class="highlighting" >development</span>, Expression of WNT4 during nephron <span class="highlighting" >development</span>, Expression of LHX1 during nephron <span class="highlighting" >development</span>, Expression of DLL1 during nephron <span class="highlighting" >development</span>, Expression of JAG1 during nephron <span class="highlighting" >development</span>, Expression of HNF4A during nephron <span class="highlighting" >development</span>, Expression of LFNG during nephron <span class="highlighting" >development</span>, BlackBoxEvent, BlackBoxEvent, BlackBoxEvent, BlackBoxEvent, BlackBoxEvent, BlackBoxEvent, BlackBoxEvent, BlackBoxEvent, BlackBoxEvent, BlackBoxEvent, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, HNF1B bound to conserved sites between the IRX2 and IRX1 genes activates expression of IRX2 in the intermediate region of the S-shaped body during <span class="highlighting" >development</span> of the nephron (inferred from mouse homologs in Heliot et al. 2013). In mice, loss of Hnf1b causes complete loss of Irx2 expression in the S-shaped body (Heliot et al. 2013)., IRX1 is expressed in the intermediate region of the S-shaped body during nephron <span class="highlighting" >development</span> (inferred from mouse embryos in Yu et al. 2012, Heliot et al. 2013, Massa et al. 2013). HNF1B binds near the IRX1 gene to activate expression (inferred from mouse homologs in Heliot et al. 2013, Massa et al. 2013)., HNF1B binds and activates expression of the WNT9B gene in the ureteric bud (inferred from mouse homologs). In mouse embryos homozygous null for Hnf1b, expression of Wnt9b is completely lost in the nephric duct and the ureteric bud (Lokmane et al. 2010). The homozygous Hnf1b mutants have severely reduced renal <span class="highlighting" >development</span>, defective ureteric branching, and few metanephric mesenchyme condensations (Lokmane et al. 2010)., POU3F3 (also called BRN1) is expressed in distal regions of renal vesicles, S-shaped bodies, and regions of the nephron that develop into the thick ascending limb and the macula densa of the loop of Henle and the distal tubule (inferred from the mouse homolog). LHX1 activates expression of POU3F3 in developing nephrons (inferred from mouse homologs). HNF1B activates expression of POU3F3 in S-shaped bodies of developing nephrons (inferred from mouse homologs). In mouse, missense mutations in Pou3f3 alters numbers and <span class="highlighting" >development</span> of nephrons (Rieger et al. 2016) and cause kidney dysfunction (Kumar et al. 2016)., WNT9B secreted from the ureteric bud induces expression of WNT4 in the surrounding metanephric mesenchyme (inferred from mouse homologs). WNT4 promotes epithelialization of pre-tubular aggregates of metanephric mesenchyme, resulting in the formation of renal vesicles. WNT9B also induces proliferation of a subset of metanephric mesenchyme to maintain a pool of nephron progenitors., WNT4 activates expression of LHX1 (also called LIM1) in metanephric mesenchyme cells in the developing nephron by a non-canonical mechanism involving calcium influx and activation of CaMKII (CAMK2A, CAMK2B, CAMK2G) (inferred from mouse homologs)., DLL1 is expressed in the distal regions of renal vesicles and comma-shaped bodies and in proximal regions of S-shaped bodies (inferred from mouse embryos). LHX1 activates DLL1 expression in renal vesicles (inferred from mouse homologs) then HNF1B enhances DLL1 expression in comma-shaped bodies and S-shaped bodies (inferred from mouse homologs)., JAG1, a ligand for NOTCH receptors, is expressed in tubules of the metanephric kidney (Crosnier et al. 2000 and inferred from mouse embryos). JAG1 is initially expressed in the distal region of renal vesicles, then HNF1B, possibly acting via DLL1 and NOTCH signaling, maintains JAG1 expression in the distal region of comma-shaped bodies and in the proximal region of S-shaped bodies (inferred from mouse homologs and embryos in Heliot et al. 2013)., HNF4A is expressed in proximal tubules of developing nephrons and is required for formation of proximal tubules (inferred from mouse embryos). In the distal region of comma-shaped bodies and the proximal region of S-shaped bodies, HNF1B binds the promoter of the HNF4A gene and activates expression of HNF4A (inferred from mouse homologs). HNF4A in turn activates expression of a large number of genes encoding metabolic enzymes, transporters, and E-cadherin (CDH1), which is involved in epithelialization (inferred from mouse homologs)., LFNG, a component glycosyltransferase of the NOTCH signaling pathway, is initially expressed at a low level in the distal region of renal vesicles (inferred from mouse embryos in Heliot et al. 2013). In subsequent comma-shaped bodies and S-shaped bodies, HNF1B binds the promoter of the LFNG gene and enhances expression (inferred from mouse homologs in Heliot et al. 2013). LFNG is expressed in the distal region of comma-shaped bodies and in the proximal region of S-shaped bodies, where it appears to play a role in the proximo-distal differentiation of nephrons (inferred from mouse embryos in Heliot et al. 2013)., nucleoplasm, nucleoplasm, nucleoplasm, extracellular region, nucleoplasm, nucleoplasm, extracellular region, nucleoplasm, nucleoplasm, plasma membrane, nucleoplasm, plasma membrane, nucleoplasm, nucleoplasm, Golgi membrane, 0005654, 0005654, 0005654, 0005576, 0005654, 0005654, 0005576, 0005654, 0005654, 0005886, 0005654, 0005886, 0005654, 0005654, 0000139, FALSE, FALSE, FALSE, FALSE, FALSE, FALSE, FALSE, FALSE, FALSE, FALSE
## 3 8865420, 2011952, 2011951, 2071952, 2071937, 2050642, 5655216, 5655328, 2050638, 5655218, R-HSA-8865420, R-HSA-2011952, R-HSA-2011951, R-HSA-2071952, R-HSA-2071937, R-HSA-2050642, R-HSA-5655216, R-HSA-5655328, R-HSA-2050638, R-HSA-5655218, R-HSA-8865420, R-HSA-2011952, R-HSA-2011951, R-HSA-2071952, R-HSA-2071937, R-HSA-2050642, R-HSA-5655216, R-HSA-5655328, R-HSA-2050638, R-HSA-5655218, RUNX2:CBFB, FGFR3c P250R mutant dimer bound to FGF, FGFR3c P250R mutant dimer, p-8Y-FGFR2c A314S dimer, FGFR2c A314S mutant dimer, Activated FGFR1c P252X mutants, Activated FGFR1 mutants:p-FRS2, FGFR1 mutants:p-FRS2:GRB2:SOS1, FGFR1c P252X mutant dimers bound to FGFs, Activated FGFR1 mutants:p-FRS2:GRB2:GAB1:PIK3R1, Complex, Complex, Complex, Complex, Complex, Complex, Complex, Complex, Complex, Complex, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, nucleoplasm, plasma membrane, plasma membrane, plasma membrane, plasma membrane, plasma membrane, plasma membrane, plasma membrane, plasma membrane, plasma membrane, 0005654, 0005886, 0005886, 0005886, 0005886, 0005886, 0005886, 0005886, 0005886, 0005886, FALSE, TRUE, TRUE, TRUE, TRUE, TRUE, TRUE, TRUE, TRUE, TRUE
## 4 199229, 6801280, 6806492, 201456, 8956775, 6807225, 6799130, 8858573, 215967, 5624196, R-HSA-199229, R-HSA-6801280, R-HSA-6806492, R-HSA-201456, R-HSA-8956775, R-HSA-6807225, R-HSA-6799130, R-HSA-8858573, R-HSA-215967, R-HSA-5624196, R-HSA-199229, R-HSA-6801280, R-HSA-6806492, R-HSA-201456, R-HSA-8956775, R-HSA-6807225, R-HSA-6799130, R-HSA-8858573, R-HSA-215967, R-HSA-5624196, SLC25A16, PRG2, PRG2, BMP2, BMP4, BGLAP(24-51), BST2, BMP4, SPP1, BST2, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, SLC25A16, PRG2, PRG2, BMP2, BMP4, BGLAP, BST2, BMP4, SPP1, BST2, P16260, P13727, P13727, P12643, P12644, P02818, Q10589, P12644, P10451, Q10589, mitochondrial inner membrane, ficolin-1-rich granule lumen, extracellular region, extracellular region, endoplasmic reticulum lumen, Golgi lumen, azurophil granule membrane, extracellular region, extracellular region, plasma membrane, 0005743, 1904813, 0005576, 0005576, 0005788, 0005796, 0035577, 0005576, 0005576, 0005886, FALSE, FALSE, FALSE, FALSE, FALSE, FALSE, FALSE, FALSE, FALSE, FALSE, UniProt, UniProt, UniProt, UniProt, UniProt, UniProt, UniProt, UniProt, UniProt, UniProt, http://purl.uniprot.org/uniprot/P16260, http://purl.uniprot.org/uniprot/P13727, http://purl.uniprot.org/uniprot/P13727, http://purl.uniprot.org/uniprot/P12643, http://purl.uniprot.org/uniprot/P12644, http://purl.uniprot.org/uniprot/P02818, http://purl.uniprot.org/uniprot/Q10589, http://purl.uniprot.org/uniprot/P12644, http://purl.uniprot.org/uniprot/P10451, http://purl.uniprot.org/uniprot/Q10589
## 5 5655215, 2050627, 2050635, 9753847, 2033358, 2012020, 2077412, 2012041, 2033383, 2018770, R-HSA-5655215, R-HSA-2050627, R-HSA-2050635, R-HSA-9753847, R-HSA-2033358, R-HSA-2012020, R-HSA-2077412, R-HSA-2012041, R-HSA-2033383, R-HSA-2018770, R-HSA-5655215, R-HSA-2050627, R-HSA-2050635, R-HSA-9753847, R-HSA-2033358, R-HSA-2012020, R-HSA-2077412, R-HSA-2012041, R-HSA-2033383, R-HSA-2018770, Activated FGFR1 mutants, p-8Y-FGFR1c P252X dimers, FGFR1c P252X mutant dimers, Activated FGFR3 point, translocation and fusion mutants, Activated FGFR3 mutants with enhanced kinase activity, Activated FGFR3 cysteine mutants, FGFR3 mutant dimers, FGFR3 cysteine mutant dimers, FGFR3 point mutant dimers with enhanced kinase activity, FGFR3 point mutants with enhanced kinase activity, DefinedSet, DefinedSet, DefinedSet, DefinedSet, CandidateSet, DefinedSet, DefinedSet, DefinedSet, CandidateSet, CandidateSet, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, plasma membrane, plasma membrane, plasma membrane, plasma membrane, plasma membrane, plasma membrane, plasma membrane, plasma membrane, plasma membrane, plasma membrane, 0005886, 0005886, 0005886, 0005886, 0005886, 0005886, 0005886, 0005886, 0005886, 0005886, TRUE, TRUE, TRUE, TRUE, TRUE, TRUE, TRUE, TRUE, TRUE, TRUE
## 6 014489, 013958, 014450, 014591, 013682, 013679, 014177, 013661, 014168, 012476, R-ICO-014489, R-ICO-013958, R-ICO-014450, R-ICO-014591, R-ICO-013682, R-ICO-013679, R-ICO-014177, R-ICO-013661, R-ICO-014168, R-ICO-012476, R-ICO-014489, R-ICO-013958, R-ICO-014450, R-ICO-014591, R-ICO-013682, R-ICO-013679, R-ICO-014177, R-ICO-013661, R-ICO-014168, R-ICO-012476, <span class="highlighting" >Bone</span> section, <span class="highlighting" >Disease</span> neuron, Neuron <span class="highlighting" >development</span>, <span class="highlighting" >Disease</span> Cell Cycle wheel, Amyloid Precursor Protein, Amyloid Beta Plaque, PRKN, GET1, ABCA4, BMPR, Icon, Icon, Icon, Icon, Icon, Icon, Icon, Icon, Icon, Icon, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Homo sapiens, Graphic representation of the section of a <span class="highlighting" >bone</span> structure., Graphic representation of a <span class="highlighting" >disease</span> affected neuron, NA, Graphic representation of the cell cycle wheel in <span class="highlighting" >disease</span>., Amyloid Precursor Protein is an integral membrane protein that can be processed into amyloid beta, which forms plaques in Alzheimer <span class="highlighting" >disease</span>, Amyloid Precursor Protein is an integral membrane protein that can be processed into amyloid beta, which forms plaques in Alzheimer <span class="highlighting" >disease</span>, E3 ubiquitin-protein ligase parkin, Guided entry of tail-anchored proteins factor 1, Retinal-specific phospholipid-transporting ATPase ABCA4, Family of <span class="highlighting" >Bone</span> morphogenetic protein receptor, Bone section, Disease neuron, Neuron development, Disease Cell Cycle wheel, Amyloid Precursor Protein, Amyloid Beta Plaque, PRKN, GET1, ABCA4, BMPR, human_tissue, cell_type, background, background, protein, protein, protein, protein, transporter, protein, receptor, Marija Orlic-Milacic, Marija Orlic-Milacic, Karen Rothfels, Marija Orlic-Milacic, Nicholas Norwitz, Nicholas Norwitz, Thawfeek Varusai, Bruce May, Bijay Jassal, Marija Orlic-Milacic, 0000-0002-3218-5631, 0000-0002-3218-5631, 0000-0002-0705-7048, 0000-0002-3218-5631, 0000-0002-0826-9069, 0000-0002-0826-9069, 0000-0002-7864-5971, 0000-0001-5193-0855, 0000-0002-5039-5405, 0000-0002-3218-5631, Cristoffer Sevilla, Cristoffer Sevilla, Cristoffer Sevilla, Cristoffer Sevilla, Sam Norwitz, Sam Norwitz, Cristoffer Sevilla, Cristoffer Sevilla, Cristoffer Sevilla, Cristoffer Sevilla, https://graphsolutions.co.uk, https://graphsolutions.co.uk, https://graphsolutions.co.uk, https://graphsolutions.co.uk, NA, NA, https://graphsolutions.co.uk, https://graphsolutions.co.uk, https://graphsolutions.co.uk, https://graphsolutions.co.uk, 0001474, UBERON:0001474, 0000540, CL:0000540, P05067, UNIPROT:P05067, P05067, UNIPROT:P05067, O60260, UNIPROT:O60260, O00258, UNIPROT:O00258, P78363, UNIPROT:P78363, P36894, UNIPROT:P36894, R-HSA-9673013, R-HSA-1643685, R-HSA-9005891, R-HSA-9605308, R-HSA-9697154, R-HSA-9675126, R-HSA-9687139, R-HSA-9734009, R-HSA-9663891, R-HSA-9609507, R-HSA-2474795, R-HSA-9006936, NA, NA, NA, NA, 0000-0002-8803-6475, 0000-0002-8803-6475, NA, NA, NA, NA, R-HSA-9839084, R-HSA-8956696, R-HSA-9839060, R-HSA-5693003, R-HSA-9010033, R-HSA-5229077, R-HSA-49335, R-HSA-8871509, R-HSA-9010038, R-HSA-139835, R-HSA-5229136, R-HSA-877188, R-HSA-6783333, R-HSA-976740, R-HSA-5692993, R-HSA-879340, R-HSA-9010082, R-HSA-9010028, R-HSA-6783331, R-HSA-6783325, R-HSA-9617603, R-HSA-8957012, ReferenceIsoform, ReferenceGeneProduct, ReferenceIsoform, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, APP (535-695), APP, APP, APP(18-671), APP(18-687), APP(18-770), APP(18-770), APP(18-770), APP(18-770), APP(18-770), APP(18-770), APP(672-711), APP(672-711), APP(672-711), APP(672-713), APP(672-713), APP(672-770), APP(688-770), APP(712-770), APP(714-770), APP-C99, p-APP, cytosol, endoplasmic reticulum lumen, mitochondrial inner membrane, endosome lumen, extracellular region, endosome lumen, extracellular region, Golgi lumen, plasma membrane, platelet alpha granule lumen, trans-Golgi network membrane, cytosol, endosome lumen, extracellular region, endosome lumen, extracellular region, endosome lumen, plasma membrane, endosome lumen, endosome lumen, cytosol, endoplasmic reticulum lumen, APP (535-695) [cytosol], APP [endoplasmic reticulum lumen], APP [mitochondrial inner membrane], APP(18-671) [endosome lumen], APP(18-687) [extracellular region], APP(18-770) [endosome lumen], APP(18-770) [extracellular region], APP(18-770) [Golgi lumen], APP(18-770) [plasma membrane], APP(18-770) [platelet alpha granule lumen], APP(18-770) [trans-Golgi network membrane], APP(672-711) [cytosol], APP(672-711) [endosome lumen], APP(672-711) [extracellular region], APP(672-713) [endosome lumen], APP(672-713) [extracellular region], APP(672-770) [endosome lumen], APP(688-770) [plasma membrane], APP(712-770) [endosome lumen], APP(714-770) [endosome lumen], APP-C99 [cytosol], p-APP [endoplasmic reticulum lumen], R-HSA-9839084, R-HSA-8956696, R-HSA-9839060, R-HSA-5693003, R-HSA-9010033, R-HSA-5229077, R-HSA-49335, R-HSA-8871509, R-HSA-9010038, R-HSA-139835, R-HSA-5229136, R-HSA-877188, R-HSA-6783333, R-HSA-976740, R-HSA-5692993, R-HSA-879340, R-HSA-9010082, R-HSA-9010028, R-HSA-6783331, R-HSA-6783325, R-HSA-9617603, R-HSA-8957012, ReferenceIsoform, ReferenceGeneProduct, ReferenceIsoform, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, 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APP (535-695) [cytosol], APP [endoplasmic reticulum lumen], APP [mitochondrial inner membrane], APP(18-671) [endosome lumen], APP(18-687) [extracellular region], APP(18-770) [endosome lumen], APP(18-770) [extracellular region], APP(18-770) [Golgi lumen], APP(18-770) [plasma membrane], APP(18-770) [platelet alpha granule lumen], APP(18-770) [trans-Golgi network membrane], APP(672-711) [cytosol], APP(672-711) [endosome lumen], APP(672-711) [extracellular region], APP(672-713) [endosome lumen], APP(672-713) [extracellular region], APP(672-770) [endosome lumen], APP(688-770) [plasma membrane], APP(712-770) [endosome lumen], APP(714-770) [endosome lumen], APP-C99 [cytosol], p-APP [endoplasmic reticulum lumen], R-HSA-9834954, R-HSA-9793481, R-HSA-5689094, R-HSA-201579, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, p-S65-PRKN, p-S9-PRKN, polyUb-PARK2, PRKN, cytosol, cytosol, cytosol, cytosol, p-S65-PRKN [cytosol], p-S9-PRKN [cytosol], polyUb-PARK2 [cytosol], PRKN [cytosol], R-HSA-9609521, ReferenceGeneProduct, WRB, endoplasmic reticulum membrane, WRB [endoplasmic reticulum membrane], R-HSA-1457539, R-HSA-2466850, R-HSA-2466780, R-HSA-2466821, R-HSA-2466827, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ABCA4, ABCA4 A1028V, ABCA4 G1961E, ABCA4 G863A, ABCA4 R943Q, photoreceptor disc membrane, photoreceptor disc membrane, photoreceptor disc membrane, photoreceptor disc membrane, photoreceptor disc membrane, ABCA4 [photoreceptor disc membrane], ABCA4 A1028V [photoreceptor disc membrane], ABCA4 G1961E [photoreceptor disc membrane], ABCA4 G863A [photoreceptor disc membrane], ABCA4 R943Q [photoreceptor disc membrane], R-HSA-201480, R-HSA-201448, ReferenceGeneProduct, ReferenceGeneProduct, BMPR1A, p-4S-BMPR1A, plasma membrane, plasma membrane, BMPR1A [plasma membrane], p-4S-BMPR1A [plasma membrane]
## typeName entriesCount rowCount
## 1 Pathway 826 10
## 2 Reaction 1796 10
## 3 Complex 330 10
## 4 Protein 536 10
## 5 Set 114 10
## 6 Icon 27 10# the entries dataframe for the first row, with typeName 'Pathway'
(bdd.search[["results"]])[[1]][[1]]## dbId stId id
## 1 8941326 R-HSA-8941326 R-HSA-8941326
## 2 1643685 R-HSA-1643685 R-HSA-1643685
## 3 5663205 R-HSA-5663205 R-HSA-5663205
## 4 9830369 R-HSA-9830369 R-HSA-9830369
## 5 9831926 R-HSA-9831926 R-HSA-9831926
## 6 5655302 R-HSA-5655302 R-HSA-5655302
## 7 1226099 R-HSA-1226099 R-HSA-1226099
## 8 5655253 R-HSA-5655253 R-HSA-5655253
## 9 5655332 R-HSA-5655332 R-HSA-5655332
## 10 5655291 R-HSA-5655291 R-HSA-5655291
## name
## 1 RUNX2 regulates <span class="highlighting" >bone</span> <span class="highlighting" >development</span>
## 2 <span class="highlighting" >Disease</span>
## 3 Infectious <span class="highlighting" >disease</span>
## 4 Kidney <span class="highlighting" >development</span>
## 5 Nephron <span class="highlighting" >development</span>
## 6 Signaling by FGFR1 in <span class="highlighting" >disease</span>
## 7 Signaling by FGFR in <span class="highlighting" >disease</span>
## 8 Signaling by FGFR2 in <span class="highlighting" >disease</span>
## 9 Signaling by FGFR3 in <span class="highlighting" >disease</span>
## 10 Signaling by FGFR4 in <span class="highlighting" >disease</span>
## exactType species
## 1 Pathway Homo sapiens
## 2 TopLevelPathway Homo sapiens
## 3 Pathway Homo sapiens
## 4 Pathway Homo sapiens
## 5 Pathway Homo sapiens
## 6 Pathway Homo sapiens
## 7 Pathway Homo sapiens
## 8 Pathway Homo sapiens
## 9 Pathway Homo sapiens
## 10 Pathway Homo sapiens
## summation
## 1 RUNX2 is required for the <span class="highlighting" >development</span> of both intramembraneous and endochondral bones through regulation of osteoblast differentiation and chondrocyte maturation, respectively. In its absence, intramembraneous ossification is blocked while endochondral ossification is arrested at the cartilaginous stage (Otto et al. 1997, Komori et al. 1997). In mice and humans, RUNX2 haploinsufficiency causes Cleidocranial dysplasia, a generalized <span class="highlighting" >bone</span> disorder (Otto et al. 1997, Lee et al. 1997).<br>RUNX2 stimulates transcription of most of the genes constituting the <span class="highlighting" >bone</span> extracellular matrix and of BGLAP gene, which encodes Osteocalcin, a <span class="highlighting" >bone</span>-derived hormone controlling glucose metabolism, male fertility and cognition (Ducy et al. 1997).<br>RUNX2 promotes chondrocyte maturation by stimulating transcription of the IHH gene, encoding Indian hedgehog (Takeda et al. 2001, Yoshida et al. 2004).<br>In response to BMP2 signaling, RUNX2 forms a complex with SMAD1:SMAD4 heterotrimer in the nucleus and stimulates transcription of SMAD6 (Wang et al. 2007).<br>RBM14, a negative regulator of RUNX2 transcriptional activity, is frequently overexpressed in osteosarcoma (Li et al. 2009).
## 2 Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human <span class="highlighting" >disease</span> pathways have three mechanistic causes: the inclusion of microbially-expressed proteins, altered functions of human proteins, or changed expression levels of otherwise functionally normal human proteins.<p>The first group encompasses the infectious diseases such as influenza, tuberculosis and HIV infection. The second group involves human proteins modified either by a mutation or by an abnormal post-translational event that produces an aberrant protein with a novel function. Examples include somatic mutations of EGFR and FGFR (epidermal and fibroblast growth factor receptor) genes, which encode constitutively active receptors that signal even in the absence of their ligands, or the somatic mutation of IDH1 (isocitrate dehydrogenase 1) that leads to an enzyme active on 2-oxoglutarate rather than isocitrate, or the abnormal protein aggregations of amyloidosis which lead to diseases such as Alzheimer's.<p>Infectious diseases are represented in Reactome as microbial-human protein interactions and the consequent events. The existence of variant proteins and their association with <span class="highlighting" >disease</span>-specific biological processes is represented by inclusion of the modified protein in a new or variant reaction, an extension to the 'normal' pathway. Diseases which result from proteins performing their normal functions but at abnormal rates can also be captured, though less directly. Many mutant alleles encode proteins that retain their normal functions but have abnormal stabilities or catalytic efficiencies, leading to normal reactions that proceed to abnormal extents. The phenotypes of such diseases can be revealed when pathway annotations are combined with expression or rate data from other sources.<br><br>Depending on the biological pathway/process immediately affected by <span class="highlighting" >disease</span>-causing gene variants, non-infectious diseases in Reactome are organized into diseases of signal transduction by growth factore receptors and second messengers, diseases of mitotic cell cycle, diseases of cellular response to stress, diseases of programmed cell death, diseases of DNA repair, disorders of transmembrane transporters, diseases of metabolism, diseases of immune system, diseases of neuronal system, disorders of developmental biology, disorders of extracellular matrix organization, and diseases of hemostatis.
## 3 Infectious diseases are ones due to the presence of pathogenic microbial agents in human host cells. Processes annotated in this category include bacterial, viral and parasitic infection pathways.<br><br>Bacterial infection pathways currently include some metabolic processes mediated by intracellular Mycobacterium tuberculosis, the actions of clostridial, anthrax, and diphtheria toxins, and the entry of Listeria monocytogenes into human cells.<br><br>Viral infection pathways currently include the life cycles of SARS-CoV viruses, influenza virus, HIV (human immunodeficiency virus), and human cytomegalovirus (HCMV).<br><br>Parasitic infection pathways currently include Leishmania infection-related pathways.<br><br>Fungal infection pathways and prion diseases have not been annotated.
## 4 Kidney <span class="highlighting" >development</span> begins at embryonic day 8.5 (E8.5) in mouse embryos, a time after gastrulation and formation of the intermediate mesoderm (reviewed in Marcotte et al. 2014, Smyth 2021, Schnell et al. 2022). Renal progenitors are specified within the intermediate mesoderm in the region between the 6th and 8th somites. The nephric duct then begins to form by mesenchymal to epithelial transitions of the renal progenitors and grows caudally to fuse with the bladder and urethra primordium (cloaca). The nephric duct induces the formation of mesonephric tubules in the adjacent nephric cord which form the mesonephros, an embryonic kidney in mammals that regresses and is supplanted by the metanephros. (In anamniotes such as frogs and fish, the mesonephros is the adult kidney and no metanephros forms.) <br>In mammals, the metanephros is initiated as the caudal region of the nephric cord forms metanephric mesenchyme which then interacts with the nephric duct to induce formation of the ureteric bud, the progenitor of the ureter. Branching of the ureteric bud forms ureter tips which induce nephron formation in the surrounding metanephric mesenchyme (reviewed in El-Dahr et al. 2008, O'Brien and McMahon 2014, Desgrange and Cereghini 2015, Chambers and Wingert 2020, Schnell et al. 2022). <br>Induction of kidney <span class="highlighting" >development</span> in the intermediate mesoderm occurs by incompletely characterized signals from the adjacent ectoderm and lateral plate mesoderm. Notably, BMP activity from the lateral plate mesoderm can induce expression of the renal markers Pax2 and Lhx1.<br>Foxc1 and Foxc2 expressed in the paraxial mesoderm repress Lhx1 and prevent over-expansion of the intermediate mesoderm (Wilm et al. 2004). Conversely, Nodal signaling maintains Pax2 expression and prevents over-expansion of the paraxial mesoderm (Fleming et al. 2013). The rostral-caudal position of renal <span class="highlighting" >development</span> appears to specified by the rostral-caudal gradient of retinoic acid acting through HoxB4 (Preger-Ben Noon et al. 2009) and limited caudally by HoxA6. <br>The combined expression of Pax2, Pax8, Lhx1, and Gata3 is the earliest observed marker of the renal lineage and these transcription factors, together with Emx2, form a self-reinforcing module that drives formation of the nephric duct. Nephronectin (Npnt) from the nephric duct interacts with integrin alpha8/beta1 (Itga8) on the metanephric mesenchyme and Ret located on the nephric duct interacts with Gdnf secreted by the metanephric mesenchyme to regulate formation and branching of the ureteric bud (reviewed in Marcotte et al. 2014). Signals from the tips of the ureteric bud then induce epithelialization of the metanephric mesenchyme and formation of nephrons, the basic filtration units of the kidney comprising the glomerulus, the proximal tubule, the loop of Henle, and the distal tubule (reviewed in Desgrange and Cereghini 2015). Canonical Wnt signaling from the ureteric bud appears to be the main inductive event: Wnt9b activates Wnt4 expression to epithelialize mesenchymal pre-tubular aggregates and Wnt9b also supports expression of Six2 to maintain a nephron progenitor pool in the cap mesenchyme.<br>Congenital anomalies of the kidney and urinary tract (CAKUT) comprise about 30% of antnatal congenital abnormalities and cause the majority of chronic kidney <span class="highlighting" >disease</span> in children (reviewed in Costigan and Rosenblum 2022). Knowledge gained from studying kidney <span class="highlighting" >development</span> is being used to generate kidney organoids in vitro with a goal of producing transplantable kidney tissue (reviewed in Kalejaiye et al. 2022, Safi et al. 2022, Trush and Takasato 2022, Shi et al. 2023).
## 5 A nephron of an amniote such as mouse or human comprises the glomerulus where small molecules are filtered out of the blood, the proximal tubule and the loop of Henle where small molecules are selectively reabsorbed, the thick ascending limb, the macula densa, the distal convoluted tubule, the connecting tubule, and the collecting duct which drains into the ureter.<br>Initiation of nephron <span class="highlighting" >development</span> occurs at the termini of the branches of the ureteric bud where cells of the ureteric bud interact with cells of the metanephric mesenchyme. Rather than differentiating in place, analysis of cellular migration indicates that progenitors are recruited from the mesenchyme to the developing epithelial elements of the nephron (Lindstrom et al. 2018). The transcriptional program that operates during human nephrogenesis has been mapped in extraordinary detail (Lindstrom et al. 2021). WNT9B secreted by the ureteric bud induces a subset of renal progenitor cells to aggregate and express WNT4, which causes the pre-tubular aggregates to further undergo a mesenchymal to epithelial transition to form renal vesicles (inferred from mouse embryos in Park et al. 2007, reviewed in El-Dahr et al. 2008, Costantini and Kopan 2010, Desgrange and Cereghini 2015). A subset of renal progenitor cells express SIX2 and respond to WNT9B by proliferating to maintain a renewing population of renal progenitors. The reason for the difference in responses may be the local concentration of WNT9B (inferred from mouse embryos in Ramalingam et al. 2018) or the presence of the transcription factor SIX2 (inferred from mouse embryos in Karner et al. 2011).<br>The renal vesicle becomes polarized early. The distal region contains a gene regulatory network containing LHX1, POU3F3 (BRN1), DLL1, and JAG1. LHX1 is required for proximo-distal differentiation (inferred from mouse embryos in Kobayashi et al. 2005) and POU3F3 participates in elongation of the loop of Henle and formation of the distal convoluted tubule (inferred from mouse embryos in Nakai et al. 2003). The proximal region of the renal vesicle expresses WT1, which directly represses PAX2 to enable formation of podocytes (inferred from mouse homologs in Ryan et al. 1995). The renal vesicle develops into the comma-shaped body in which HNF1B in the distal region activates NOTCH pathway components DLL1, JAG1, and LFNG (inferred from mouse embryos in Heliot et al. 2013). The comma-shaped body in turn develops into the S-shaped body in which HNF1B activates IRX1 and IRX2 in the intermediate region (inferred from mouse embryos in Heliot et al. 2013). Podocytes, the proximal tubule, the intermediate tubule, and the distal tubule then differentiate.
## 6 The FGFR1 gene has been shown to be subject to activating mutations, chromosomal rearrangements and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007; Wesche, 2011; Greulich and Pollock, 2011). <br><br><br>Activating mutation P252R in FGFR1 is associated with the <span class="highlighting" >development</span> of Pfeiffer syndrome, characterized by craniosynostosis (premature fusion of several sutures in the skull) and broadened thumbs and toes (Muenke, 1994; reviewed in Cunningham, 2007). This residue falls in a highly conserved Pro-Ser dipeptide between the second and third Ig domains of the extracellular region of the receptor. The mutation is thought to increase the number of hydrogen bonds formed with the ligand and to thereby increase ligand-binding affinity (Ibrahimi, 2004a). Unlike other FGF receptors, few activating point mutations in the FGFR1 coding sequence have been identified in cancer. Point mutations in the Ig II-III linker analagous to the P252R Pfeiffer syndrome mutation have been identified in lung cancer and melanoma (Ruhe, 2007; Davies, 2005), and two kinase-domain mutations in FGFR1 have been identified in glioblastoma (Rand, 2005, Network TCGA, 2008).<br><br>In contrast, FGFR1 is a target of chromosomal rearrangements in a number of cancers. FGFR1 has been shown to be recurrently translocated in the 8p11 myeloproliferative syndrome (EMS), a pre-leukemic condition also known as stem cell leukemia/lymphoma (SCLL) that rapidly progresses to leukemia. This translocation fuses the kinase domain of FGFR1 with the dimerization domain of one of 10 identified fusion partners, resulting in the constitutive dimerization and activation of the kinase (reviewed in Jackson, 2010). <br><br>Amplification of the FGFR1 gene has been implicated as a oncogenic factor in a range of cancers, including breast, ovarian, bladder, lung, oral squamous carcinomas, and rhabdomyosarcoma (reviewed in Turner and Grose, 2010; Wesche, 2011; Greulich and Pollock, 2011), although there are other candidate genes in the amplified region and the definitive role of FGFR1 has not been fully established.<br>More recently, FGFR1 fusion proteins have been identified in a number of cancers; these are thought to undergo constitutive ligand-independent dimerization and activation based on dimerization motifs found in the fusion partners (reviewed in Parker, 2014).
## 7 A number of skeletal and developmental diseases have been shown to arise as a result of mutations in the FGFR1, 2 and 3 genes. These include dwarfism syndromes (achondroplasia, hypochondroplasia and the neonatal lethal disorders thanatophoric dysplasia I and II), as well as craniosynostosis disorders such as Pfeiffer, Apert, Crouzon, Jackson-Weiss and Muenke syndromes (reviewed in Webster and Donoghue 1997; Burke, 1998, Cunningham, 2007; Harada, 2009). These mutations fall into four general regions of the receptor: a) the immunoglobulin (Ig)-like domain II-III linker region, b) the alternatively spliced second half of the Ig III domain, c) the transmembrane domain and d) the tyrosine kinase domain (reviewed in Webster and Donoghue, 1997). With the exception of mutations in class b), which affect only the relevant splice variant, these mutations may be present in either the 'b' or 'c' isoforms. These activating mutations affect FGFR function by altering or expanding the ligand-binding range of the receptors (see for instance Ibrahimi, 2004a), by promoting ligand-independent dimerization (for instance, Galvin,1996; Neilson and Friesel, 1996; d'Avis,1998) or by increasing the activity of the kinase domain (for instance, Webster, 1996; Naski, 1996; Tavormina, 1999; Bellus, 2000). Thus, a number of the point mutations found in FGFR receptors alter their activity without altering their intrinsic kinase activity. Many of the mutations that promote constitutive dimerization do so by creating or removing cysteine residues; the presence of an unpaired cysteine in the receptor is believed to promote dimerization through the formation of intramolecular disulphide bonds (Galvin, 1996; Robertson, 1998). Paralogous mutations at equivalent positions have been identified in more than one FGF receptor, sometimes giving rise to different diseases. For instance, mutation of the highly conserved FGFR2 Ser252-Pro253 dipeptide in the region between the second and third Ig domain is responsible for virtually all cases of Apert Syndrome (Wilkie, 1995), while paralogous mutations in FGFR1 (S252R) and FGFR3 (P250R) are associated with Pfeiffer and Crouzon syndromes, respectively (Bellus, 1996). FGFR4 is unique in that mutations of this gene are not known to be associated with any developmental disorders.<br><br>Recently, many of the same activating mutations in the FGFR genes that have been characterized in skeletal and developmental disorders have begun to be identified in a range of cancers (reviewed in Turner and Gross, 2010; Greulich and Pollock, 2011; Wesche, 2011). The best established link between a somatic mutation of an FGFR and the <span class="highlighting" >development</span> of cancer is in the case of FGFR3, where 50% of bladder cancers have mutations in the FGFR3 coding sequence. Of these mutations, which largely match the activating mutations seen in thanatophoric dysplasias, over half occur at a single residue (S249C) (Cappellen, 1999; van Rhijn, 2002). Activating mutations have also been identified in the coding sequences of FGFR1, 2 and 4 (for review, see Wesche, 2011)<br><br>In addition to activating point mutations, the FGFR1, 2 and 3 genes are subject to misregulation in cancer through gene amplification and translocation events, which are thought to lead to overexpression and ligand-independent dimerization (Weiss, 2010; Turner, 2010; Kunii, 2008; Takeda, 2007; Chesi, 1997; Avet-Loiseau, 1998; Ronchetti, 2001). It is important to note, however, that in each of these cases, the amplification or translocation involve large genomic regions encompassing additional genes, and the definitive roles of the FGFR genes in promoting oncogenesis has not been totally established. In the case of FGFR1, translocation events also give rise to FGFR1 fusion proteins that contain the intracellular kinase domain of the receptor fused to a dimerization domain from the partner gene. These fusions, which are expressed in a pre-leukemic myeloproliferative syndrome, dimerize constitutively based on the dimerization domain provided by the fusion partner and are constitutively active (reviewed in Jackson, 2010).<br><br>
## 8 The FGFR2 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically. Activating FGFR2 mutations in the germline give rise to a range of craniosynostotic conditions including Pfeiffer, Apert, Jackson-Weiss, Crouzon and Beare-Stevensen Cutis Gyrata syndromes. These autosomal dominant skeletal disorders are characterized by premature fusion of several sutures in the skull, and in some cases also involve syndactyly (abnormal <span class="highlighting" >bone</span> fusions in the hands and feet) (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007). <br><br>Activating FGFR2 mutations arising somatically have been linked to the <span class="highlighting" >development</span> of gastric and endometrial cancers (reviewed in Greulich and Pollock, 2011; Wesche, 2011). Many of these mutations are similar or identical to those that contribute to the autosomal disorders described above. Notably, loss-of-function mutations in FGFR2 have also been recently described in melanoma (Gartside, 2009). FGFR2 may also contribute to tumorigenesis through overexpression, as FGFR2 has been identified as a target of gene amplification in gastric and breast cancers (Kunii, 2008; Takeda, 2007).
## 9 The FGFR3 gene has been shown to be subject to activating mutations and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically. <br><br>Activating mutations in FGFR3 are associated with the <span class="highlighting" >development</span> of a range of skeletal dysplasias that result in dwarfism (reviewed in Webster and Donoghue, 1997; Burke et al, 1998; Harada et al, 2009). The most common form of human dwarfism is achondroplasia (ACH), which is caused by mutations G380R and G375C in the transmembrane domain of FGFR3 that are thought to promote ligand-independent dimerization (Rousseau et al, 1994; Shiang et al, 1994; Bellus et al, 1995a) Hypochondroplasia (HCH) is a milder form dwarfism that is the result of mutations in the tyrosine kinase domain of FGFR3 (Bellus et al, 1995b). Two neonatal lethal conditions, thanatophoric dysplasia type I and II (TDI and TDII) are also the result of mutations in FGFR3; TDI arises from a range of mutations that either result in the formation of unpaired cysteine residues in the extracellular region that promote aberrant ligand-independent dimerization or by mutations that introduce stop codons (Rousseau et al, 1995; Rousseau et al, 1996, D'Avis et al,1998). A single mutation, K650E in the second tyrosine kinase domain of FGFR3 is responsible for all identified cases of TDII (Tavormina et al, 1995a, b). Other missense mutations at the same K650 residue give rise to Severe Achondroplasia with Developmental Disorders and Acanthosis Nigricans (SADDAN) syndrome (Tavormina et al, 1999; Bellus et al, 1999). The severity of the phenotype arising from many of the activating FGFR3 mutations has recently been shown to correlate with the extent to which the mutations activate the receptor (Naski et al, 1996; Bellus et al, 2000) <br><br>In addition to mutations that cause dwarfism syndromes, a Pro250Arg mutation in the conserved dipeptide between the IgII and IgIII domains has been identified in an atypical craniosynostosis condition (Bellus et al, 1996; Reardon et al, 1997). This mutation, which is paralogous to mutations seen in FGFR1 and 2 in Pfeiffer and Apert Syndrome, respectively, results in an increase in ligand-binding affinity for the receptor (Ibrahimi et al, 2004b).<br><br><br>Of all the FGF receptors, FGFR3 has perhaps the best established link to the <span class="highlighting" >development</span> in cancer. 50% of bladder cancers have somatic mutations in the coding sequence of FGFR3; of these, more than half occur in the extracellular region at a single position (S249C) (Cappellen et al, 1999; Naski et al, 1996; di Martino et al, 2009, Sibley et al, 2001). Activating mutations are also seen in the juxta- and trans-membrane domains, as well as in the kinase domain (reviewed in Weshe et al, 2011). As is the case for the other receptors, many of the activating mutations that are seen in FGFR3-related cancers mimic the germline FGFR3 mutations that give rise to autosomal skeletal disorders and include both ligand-dependent and independent mechanisms (reviewed in Webster and Donoghue, 1997; Burke et al, 1998). In addition to activating mutations, the FGFR3 gene is subject to a translocation event in 15% of multiple myelomas (Avet-Loiseau et al, 1998; Chesi et al, 1997). This chromosomal rearrangement puts the FGFR3 gene under the control of the highly active IGH promoter and promotes overexpression and constitutive activation of FGFR3. In a small proportion of multiple myelomas, the translocation event is accompanied by activating mutations in the FGFR3 coding sequence (Chesi et al, 1997).<br><br>More recently, a number of fusion proteins of FGFR3 have been identified in various cancers (Singh et al, 2012; Williams et al, 2013; Parker et al, 2013; Wu et al, 2013; Wang et al, 2014; Yuan et al, 2014; reviewed in Parker et al, 2014). The most common fusion protein is TACC3, a coiled coil protein involved in mitotic spindle assembly. FGFR3 fusion proteins are constitutively active and appear to contribute to proliferation and tumorigenesis through activation of the ERK and AKT signaling pathways (reviewed in Parker et al, 2014).
## 10 FGFR4 is perhaps the least well studied of the FGF receptors, and unlike the case for the other FGFR genes, mutations in FGFR4 are not known to be associated with any developmental disorders. Recently, however, somatically arising mutations in the FGFR4 coding sequence have begun to be identified in some cancers. 8% of rhabdomyosarcomas have activating mutations in the kinase domain of FGFR4. Two of these mutations - N535K (paralogous to the FGFR2 N550K allele found in endometrial cancers) and V550E - have been shown to support the oncogenic transformation of NIH 3T3 cells (Taylor, 2009). An FGFR4 Y367C mutation has also been identified in breast cancers (Ruhe, 2007; Roidl, 2010); mutations of paralogous residues in FGFR2 and FGFR3 are associated with both skeletal dysplasias and the <span class="highlighting" >development</span> of diverse cancers (Pollock, 2007; Ruhe, 2007; Rousseau, 1996; Chesi, 1997, 2001).<br><br><br>Finally, a SNP at position 388 of FGFR4 is associated with aggressive <span class="highlighting" >disease</span> <span class="highlighting" >development</span>. Expression of the G388R allele in breast, colorectal and prostate cancers is correlated with rapid progression times and increased rates of recurrence and metastasis (Bange, 2002; Spinola, 2005; Wang, 2004).
## isDisease
## 1 FALSE
## 2 TRUE
## 3 TRUE
## 4 FALSE
## 5 FALSE
## 6 TRUE
## 7 TRUE
## 8 TRUE
## 9 TRUE
## 10 TRUEThe result instances are primarily faceted by types available for this query term. As such, you could know what pathways (the above dataframe), reactions, proteins, etc. are related to the bone development disease in human.
Filters in searchQuery() include species,
types, compartments, keywords;
all the items for filtering can be viewed using function
listSearchItems. For more details, see
?listSearchItems.
Participants of Event
Events represent biological processes and are further subclassed into Pathways and ReactionLikeEvents in Reactome. ReactionLikeEvents are single-step molecular transformations. Pathways are ordered groups of ReactionLikeEvents that together carry out a biological process.
Participants of a given Event (e.g. reactions of a
pathway, participating molecules of a reaction) can be retrieved using
function getParticipants. Some explanations on the
retrieval options in this function:
AllInstances: retrieve all PhysicalEntities and collections of ReferenceEntities. For entities in a ReactionLikeEvent, there would be additional columnstypeandnumOfEntriesto indicate what are inputs, outputs, catalysts, regulators, and the number of these componentsEventsInPathways: retrieve all ReactionLikeEvents and subpathways in a given PathwayPhysicalEntities/ReferenceEntities: retrieve all contained PhysicalEntities/ReferenceEntities of all PhysicalEntities of a given Event
To be more specific, PhysicalEntity instances contain numerous invariant features such as names, molecular structure and links to external databases like UniProt or ChEBI. Thus, Reactome creates instances of the separate ReferenceEntity class that support PhysicalEntity instances. All PhysicalEntity instances have a linked ReferenceEntity instance that captures reference features (such as external identifiers) of a molecule.
Events in Pathways
Since we’ve known several pathways related to the bone development disease from above results, we might further retrieve ReactionLikeEvents and Pathways in the “hasEvent” attribute of Pathway “Signaling by FGFR1 in disease” (stId R-HSA-5655302):
# Get sub-Events of an Event
fgfr1.signal.reactions <- getParticipants("R-HSA-5655302", retrieval = "EventsInPathways")
head(fgfr1.signal.reactions, 5)## dbId displayName
## 1 1839100 p-4Y- PLCG1 dissociates from activated FGFR1 mutants and fusions
## 2 5655269 Activated FGFR1 mutants bind FRS2
## 3 5655266 Activated FGFR1 mutants:p-FRS2 binds GRB2-SOS1
## 4 1839098 Activated FGFR1 mutants and fusions phosphorylate PLCG1
## 5 1839124 FGFR1 mutant receptor activation
## stId stIdVersion isInDisease isInferred
## 1 R-HSA-1839100 R-HSA-1839100.3 TRUE FALSE
## 2 R-HSA-5655269 R-HSA-5655269.2 TRUE FALSE
## 3 R-HSA-5655266 R-HSA-5655266.2 TRUE FALSE
## 4 R-HSA-1839098 R-HSA-1839098.3 TRUE FALSE
## 5 R-HSA-1839124 R-HSA-1839124.4 TRUE FALSE
## name releaseDate
## 1 p-4Y- PLCG1 dissociates from activated FGFR1 mutants and fusions 2012-06-12
## 2 Activated FGFR1 mutants bind FRS2 2012-06-12
## 3 Activated FGFR1 mutants:p-FRS2 binds GRB2-SOS1 2012-06-12
## 4 Activated FGFR1 mutants and fusions phosphorylate PLCG1 2012-06-12
## 5 FGFR1 mutant receptor activation 2012-06-12
## speciesName isChimeric category className schemaClass hasDiagram hasEHLD
## 1 Homo sapiens FALSE dissociation Reaction Reaction NA NA
## 2 Homo sapiens FALSE binding Reaction Reaction NA NA
## 3 Homo sapiens FALSE binding Reaction Reaction NA NA
## 4 Homo sapiens FALSE transition Reaction Reaction NA NA
## 5 Homo sapiens NA <NA> Pathway Pathway FALSE FALSE
## lastUpdatedDate
## 1 <NA>
## 2 <NA>
## 3 <NA>
## 4 <NA>
## 5 2019-03-25Instances in Reactions
For a ReactionLikeEvent, say “Activated FGFR1 mutants and fusions phosphorylate PLCG1” with identifier R-HSA-1839098, all relative PhysicalEntities and ReferenceEntities could be retrieved:
# Get all Entities of a ReactionLikeEvent
instances.1839098 <- getParticipants("R-HSA-1839098", retrieval = "AllInstances")
instances.1839098## peDbId displayName schemaClass
## 1 1839061 Activated FGFR1 mutants and fusions:PLCG1 [cytosol] Complex
## 2 113592 ATP [cytosol] SimpleEntity
## 3 1839062 Activated FGFR1 mutants and fusion:p-PLCG1 [cytosol] Complex
## 4 29370 ADP [cytosol] SimpleEntity
## type numOfEntries
## 1 input,catalyst 1
## 2 input 4
## 3 output 1
## 4 output 4
## refEntities
## 1 61708, 402793, 5654216, 54814, 1666990, 54768, 54762, 54802, 54776, 54808, 54764, 54796, 54772, 54778, 54770, 50677, 87246, 225247, 235739, 94717, 225142, 229580, 67910, 50776, 229857, 65879, 226135, 9760856, P19174, P11362, P11362-19, P11362-1, 28815, P08620, P05230, Q9NP95, P55075-1, Q9GZV9, P09038, O60258-1, P10767, P31371, P12034-1, O95429, O94905, Q16630, Q32MZ4, Q92614, Q7Z7A1-3, Q9NVK5, Q9UBW7, P11274, O95684, O15164, P39880, 57836, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceIsoform, ReferenceIsoform, ReferenceMolecule, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceIsoform, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceIsoform, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceIsoform, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceIsoform, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceMolecule, UniProt:P19174 PLCG1, UniProt:P11362 FGFR1, UniProt:P11362-19 FGFR1, UniProt:P11362-1 FGFR1, heparan sulfate [ChEBI:28815], UniProt:P08620 FGF4, UniProt:P05230 FGF1, UniProt:Q9NP95 FGF20, UniProt:P55075-1 FGF8, UniProt:Q9GZV9 FGF23, UniProt:P09038 FGF2, UniProt:O60258-1 FGF17, UniProt:P10767 FGF6, UniProt:P31371 FGF9, UniProt:P12034-1 FGF5, UniProt:O95429 BAG4, UniProt:O94905 ERLIN2, UniProt:Q16630 CPSF6, UniProt:Q32MZ4 LRRFIP1, UniProt:Q92614 MYO18A, UniProt:Q7Z7A1-3 CNTRL, UniProt:Q9NVK5 FGFR1OP2, UniProt:Q9UBW7 ZMYM2, UniProt:P11274 BCR, UniProt:O95684 CEP43, UniProt:O15164 TRIM24, UniProt:P39880 CUX1, 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) [ChEBI:57836], EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, SimpleEntity, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, SimpleEntity, http://purl.uniprot.org/uniprot/P19174, http://purl.uniprot.org/uniprot/P11362, http://purl.uniprot.org/uniprot/P11362-19, http://purl.uniprot.org/uniprot/P11362-1, http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:28815, http://purl.uniprot.org/uniprot/P08620, http://purl.uniprot.org/uniprot/P05230, http://purl.uniprot.org/uniprot/Q9NP95, http://purl.uniprot.org/uniprot/P55075-1, http://purl.uniprot.org/uniprot/Q9GZV9, http://purl.uniprot.org/uniprot/P09038, http://purl.uniprot.org/uniprot/O60258-1, http://purl.uniprot.org/uniprot/P10767, http://purl.uniprot.org/uniprot/P31371, http://purl.uniprot.org/uniprot/P12034-1, http://purl.uniprot.org/uniprot/O95429, http://purl.uniprot.org/uniprot/O94905, http://purl.uniprot.org/uniprot/Q16630, http://purl.uniprot.org/uniprot/Q32MZ4, http://purl.uniprot.org/uniprot/Q92614, http://purl.uniprot.org/uniprot/Q7Z7A1-3, http://purl.uniprot.org/uniprot/Q9NVK5, http://purl.uniprot.org/uniprot/Q9UBW7, http://purl.uniprot.org/uniprot/P11274, http://purl.uniprot.org/uniprot/O95684, http://purl.uniprot.org/uniprot/O15164, http://purl.uniprot.org/uniprot/P39880, http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:57836
## 2 8869364, 30616, ReferenceMolecule, ATP(4-) [ChEBI:30616], SimpleEntity, http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:30616
## 3 402793, 5654216, 54814, 1666990, 54768, 54762, 54802, 54776, 54808, 54764, 54796, 54772, 54778, 54770, 50677, 87246, 225247, 235739, 94717, 225142, 229580, 67910, 50776, 229857, 65879, 226135, 61708, P11362, P11362-19, P11362-1, 28815, P08620, P05230, Q9NP95, P55075-1, Q9GZV9, P09038, O60258-1, P10767, P31371, P12034-1, O95429, O94905, Q16630, Q32MZ4, Q92614, Q7Z7A1-3, Q9NVK5, Q9UBW7, P11274, O95684, O15164, P39880, P19174, ReferenceGeneProduct, ReferenceIsoform, ReferenceIsoform, ReferenceMolecule, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceIsoform, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceIsoform, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceIsoform, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceIsoform, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, ReferenceGeneProduct, UniProt:P11362 FGFR1, UniProt:P11362-19 FGFR1, UniProt:P11362-1 FGFR1, heparan sulfate [ChEBI:28815], UniProt:P08620 FGF4, UniProt:P05230 FGF1, UniProt:Q9NP95 FGF20, UniProt:P55075-1 FGF8, UniProt:Q9GZV9 FGF23, UniProt:P09038 FGF2, UniProt:O60258-1 FGF17, UniProt:P10767 FGF6, UniProt:P31371 FGF9, UniProt:P12034-1 FGF5, UniProt:O95429 BAG4, UniProt:O94905 ERLIN2, UniProt:Q16630 CPSF6, UniProt:Q32MZ4 LRRFIP1, UniProt:Q92614 MYO18A, UniProt:Q7Z7A1-3 CNTRL, UniProt:Q9NVK5 FGFR1OP2, UniProt:Q9UBW7 ZMYM2, UniProt:P11274 BCR, UniProt:O95684 CEP43, UniProt:O15164 TRIM24, UniProt:P39880 CUX1, UniProt:P19174 PLCG1, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, SimpleEntity, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, EntityWithAccessionedSequence, http://purl.uniprot.org/uniprot/P11362, http://purl.uniprot.org/uniprot/P11362-19, http://purl.uniprot.org/uniprot/P11362-1, http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:28815, http://purl.uniprot.org/uniprot/P08620, http://purl.uniprot.org/uniprot/P05230, http://purl.uniprot.org/uniprot/Q9NP95, http://purl.uniprot.org/uniprot/P55075-1, http://purl.uniprot.org/uniprot/Q9GZV9, http://purl.uniprot.org/uniprot/P09038, http://purl.uniprot.org/uniprot/O60258-1, http://purl.uniprot.org/uniprot/P10767, http://purl.uniprot.org/uniprot/P31371, http://purl.uniprot.org/uniprot/P12034-1, http://purl.uniprot.org/uniprot/O95429, http://purl.uniprot.org/uniprot/O94905, http://purl.uniprot.org/uniprot/Q16630, http://purl.uniprot.org/uniprot/Q32MZ4, http://purl.uniprot.org/uniprot/Q92614, http://purl.uniprot.org/uniprot/Q7Z7A1-3, http://purl.uniprot.org/uniprot/Q9NVK5, http://purl.uniprot.org/uniprot/Q9UBW7, http://purl.uniprot.org/uniprot/P11274, http://purl.uniprot.org/uniprot/O95684, http://purl.uniprot.org/uniprot/O15164, http://purl.uniprot.org/uniprot/P39880, http://purl.uniprot.org/uniprot/P19174
## 4 8869367, 456216, ReferenceMolecule, ADP(3-) [ChEBI:456216], SimpleEntity, http://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:456216It’s always a good option to visualize the instances in a reaction or
pathway for better elucidations. Reactome has diagrams for pathways and
reactions that provide information about connected events and their
locations. The diagram exporter in Content Service allows users to
easily export diagrams in bitmap format. More details see
?exportImage.
# Visualize above Reaction
exportImage("R-HSA-1839098", output = "reaction", format = "jpg", quality = 10)
Mappings
PhysicalEntity/Event to Events
Given either a PhysicalEntity or an Event, the top-level pathways or
lower-level pathways that contain it can be retrieved by function
getPathways. In this example, we try with the Complex
“Unwinding complex at replication fork [nucleoplasm]” with identifier
R-HSA-176949.
## dbId displayName stId stIdVersion isInDisease isInferred
## 1 176974 Unwinding of DNA R-HSA-176974 R-HSA-176974.4 FALSE FALSE
## name releaseDate speciesName hasDiagram hasEHLD lastUpdatedDate
## 1 Unwinding of DNA 2005-09-26 Homo sapiens FALSE FALSE 2017-06-22
## schemaClass className
## 1 Pathway Pathway## dbId displayName stId name stIdVersion oldStId
## 1 1640170 Cell Cycle R-HSA-1640170 Cell Cycle R-HSA-1640170.5 REACT_115566
## schemaClass speciesName releaseDate hasDiagram hasEHLD diagramWidth
## 1 TopLevelPathway Homo sapiens 2011-12-06 TRUE TRUE 651
## diagramHeight inferred inDisease doi definition
## 1 136 FALSE FALSE <NA> <NA>Non-Reactome id to Entities
Given an identifier in non-Reactome
resources, all relative ReferenceEntities could be
retrieved by function map2RefEntities. Here we focus on
gene TP53:
## List of 18
## $ dbId : int 69487
## $ displayName : chr "UniProt:P04637 TP53"
## $ databaseName : chr "UniProt"
## $ identifier : chr "P04637"
## $ name :List of 1
## ..$ : chr "TP53"
## $ otherIdentifier :List of 1
## ..$ : chr [1:273] "11738335_x_at" "11748319_x_at" "11748599_a_at" "11750514_x_at" ...
## $ url : chr "http://purl.uniprot.org/uniprot/P04637"
## $ checksum : chr "AD5C149FD8106131"
## $ comment :List of 1
## ..$ : chr "FUNCTION Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the ph"| __truncated__
## $ description :List of 1
## ..$ : chr "recommendedName: Cellular tumor antigen p53 alternativeName: Antigen NY-CO-13 alternativeName: Phosphoprotein p"| __truncated__
## $ geneName :List of 1
## ..$ : chr [1:2] "TP53" "P53"
## $ isSequenceChanged : logi FALSE
## $ keyword :List of 1
## ..$ : chr [1:31] "3D-structure" "Acetylation" "Activator" "Alternative promoter usage" ...
## $ secondaryIdentifier:List of 1
## ..$ : chr [1:27] "P53_HUMAN" "Q15086" "Q15087" "Q15088" ...
## $ sequenceLength : int 393
## $ chain :List of 1
## ..$ : chr "chain:1-393"
## $ className : chr "ReferenceGeneProduct"
## $ schemaClass : chr "ReferenceGeneProduct"This object is linked to UniProt with identifier P04637 and name
TP53. Once the Reactome dbId of a non-Reactome identifier
or name is obtained, the PhysicalEntities associated
with this non-Reactome identifier can be fetched through retrieving all
attributes using query:
# Extract PhysicalEntities of "TP53"
tp53.all.info <- query(tp53.re$dbId)
head(tp53.all.info$physicalEntity, 5)## dbId displayName stId stIdVersion
## 1 6813797 Unfolded TP53 [cytosol] R-HSA-6813797 R-HSA-6813797.1
## 2 8869337 TP53 [cytosol] R-HSA-8869337 R-HSA-8869337.2
## 3 6782509 PolyUb-TP53 [nucleoplasm] R-HSA-6782509 R-HSA-6782509.2
## 4 2997661 polySUMO2,3-K386-TP53 [nucleoplasm] R-HSA-2997661 R-HSA-2997661.2
## 5 9726318 TP53 F341C [nucleoplasm] R-HSA-9726318 R-HSA-9726318.1
## name
## 1 Unfolded TP53, Unfolded p53
## 2 TP53, p53 protein, P53_HUMAN, Cellular tumor antigen p53, Tumor suppressor p53, Phosphoprotein p53, Antigen NY-CO-13
## 3 PolyUb-TP53, TP53, p53 protein, P53_HUMAN, Cellular tumor antigen p53, Tumor suppressor p53, Phosphoprotein p53, Antigen NY-CO-13
## 4 polySUMO2,3-K386-TP53, SUMO2 N-glycyl-lys386 TP53, Cellular tumor antigen p53, P53_HUMAN
## 5 TP53 F341C
## speciesName
## 1 Homo sapiens
## 2 Homo sapiens
## 3 Homo sapiens
## 4 Homo sapiens
## 5 Homo sapiens
## species
## 1 48887, Homo sapiens, Homo sapiens, H. sapiens, Hs, human, man, 9606, 72938, NCBI_taxonomy:9606, NCBI Taxonomy, 9606, http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606, DatabaseIdentifier, DatabaseIdentifier, HSA, Species, Species
## 2 48887
## 3 48887
## 4 48887
## 5 48887
## endCoordinate referenceType startCoordinate referenceEntity className
## 1 393 ReferenceGeneProduct 1 69487 Protein
## 2 393 ReferenceGeneProduct 1 69487 Protein
## 3 393 ReferenceGeneProduct 1 69487 Protein
## 4 393 ReferenceGeneProduct 1 69487 Protein
## 5 393 ReferenceGeneProduct 1 69487 Protein
## inDisease schemaClass
## 1 FALSE EntityWithAccessionedSequence
## 2 FALSE EntityWithAccessionedSequence
## 3 FALSE EntityWithAccessionedSequence
## 4 FALSE EntityWithAccessionedSequence
## 5 TRUE EntityWithAccessionedSequence
## literatureReference
## 1 NULL
## 2 NULL
## 3 NULL
## 4 2997634, 5627513, 5626896, MDM2 promotes SUMO-2/3 modification of p53 to modulate transcriptional activity, Proteome-wide identification of SUMO2 modification sites, Uncovering global SUMOylation signaling networks in a site-specific manner, MDM2 promotes SUMO-2/3 modification of p53 to modulate transcriptional activity, Proteome-wide identification of SUMO2 modification sites, Uncovering global SUMOylation signaling networks in a site-specific manner, Cell Cycle, Sci Signal, Nat. Struct. Mol. Biol., 3176-88, rs2, 927-36, 21900752, 24782567, 25218447, 10, 7, 21, 2011, 2014, 2014, http://www.ncbi.nlm.nih.gov/pubmed/21900752, http://www.ncbi.nlm.nih.gov/pubmed/24782567, http://www.ncbi.nlm.nih.gov/pubmed/25218447, LiteratureReference, LiteratureReference, LiteratureReference, LiteratureReference, LiteratureReference, LiteratureReference
## 5 9726313, Cancer-associated p53 tetramerization domain mutants: quantitative analysis reveals a low threshold for tumor suppressor inactivation, Cancer-associated p53 tetramerization domain mutants: quantitative analysis reveals a low threshold for tumor suppressor inactivation, J Biol Chem, 252-8, 20978130, 286, 2011, http://www.ncbi.nlm.nih.gov/pubmed/20978130, LiteratureReference, LiteratureReference
## crossReference
## 1 NULL
## 2 NULL
## 3 NULL
## 4 NULL
## 5 9726325, COSMIC:COSV53575906, COSMIC, COSV53575906, https://cancer.sanger.ac.uk/cosmic/search?q=COSV53575906, DatabaseIdentifier, DatabaseIdentifierNon-Reactome id to Events
Furthermore, non-Reactome identifiers could be mapped to Reactome
Events with function map2Events, therefore we are able to
get pathways associated with TP53. If you stick to the gene
symbol, you should specify resource = "HGNC". Actually this
is same as id = P04637, resource = "UniProt". For
reactions, specify mapTo = "reactions".
# Get Pathways associated with "TP53"
tp53.pathways <- map2Events("TP53", resource = "HGNC", species = "human", mapTo = "pathways")
head(tp53.pathways, 5)## dbId displayName
## 1 111448 Activation of NOXA and translocation to mitochondria
## 2 139915 Activation of PUMA and translocation to mitochondria
## 3 1912408 Pre-NOTCH Transcription and Translation
## 4 2559580 Oxidative Stress Induced Senescence
## 5 2559584 Formation of Senescence-Associated Heterochromatin Foci (SAHF)
## stId stIdVersion isInDisease isInferred
## 1 R-HSA-111448 R-HSA-111448.5 FALSE FALSE
## 2 R-HSA-139915 R-HSA-139915.8 FALSE FALSE
## 3 R-HSA-1912408 R-HSA-1912408.7 FALSE FALSE
## 4 R-HSA-2559580 R-HSA-2559580.7 FALSE FALSE
## 5 R-HSA-2559584 R-HSA-2559584.3 FALSE FALSE
## name releaseDate
## 1 Activation of NOXA and translocation to mitochondria 2004-10-27
## 2 Activation of PUMA and translocation to mitochondria 2004-10-27
## 3 Pre-NOTCH Transcription and Translation 2012-03-13
## 4 Oxidative Stress Induced Senescence 2013-09-18
## 5 Formation of Senescence-Associated Heterochromatin Foci (SAHF) 2013-09-18
## speciesName hasDiagram hasEHLD lastUpdatedDate schemaClass className
## 1 Homo sapiens FALSE FALSE 2016-03-24 Pathway Pathway
## 2 Homo sapiens FALSE FALSE 2016-03-24 Pathway Pathway
## 3 Homo sapiens FALSE FALSE 2018-06-13 Pathway Pathway
## 4 Homo sapiens TRUE FALSE 2019-12-10 Pathway Pathway
## 5 Homo sapiens FALSE FALSE 2013-12-31 Pathway Pathway
## doi
## 1 <NA>
## 2 <NA>
## 3 10.3180/R-HSA-1912408.3
## 4 <NA>
## 5 <NA>Entity to non-Reactome ids
A recap for all slots of TP53 Reactome object:
## List of 25
## $ dbId : int 69487
## $ displayName : chr "UniProt:P04637 TP53"
## $ modified :List of 6
## $ databaseName : chr "UniProt"
## $ identifier : chr "P04637"
## $ name : chr "TP53"
## $ otherIdentifier : chr [1:273] "11738335_x_at" "11748319_x_at" "11748599_a_at" "11750514_x_at" ...
## $ url : chr "http://purl.uniprot.org/uniprot/P04637"
## $ crossReference :'data.frame': 321 obs. of 7 variables:
## $ referenceDatabase :List of 8
## $ physicalEntity :'data.frame': 1329 obs. of 16 variables:
## $ checksum : chr "AD5C149FD8106131"
## $ comment : chr "FUNCTION Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the ph"| __truncated__
## $ description : chr "recommendedName: Cellular tumor antigen p53 alternativeName: Antigen NY-CO-13 alternativeName: Phosphoprotein p"| __truncated__
## $ geneName : chr [1:2] "TP53" "P53"
## $ isSequenceChanged : logi FALSE
## $ keyword : chr [1:31] "3D-structure" "Acetylation" "Activator" "Alternative promoter usage" ...
## $ secondaryIdentifier: chr [1:27] "P53_HUMAN" "Q15086" "Q15087" "Q15088" ...
## $ sequenceLength : int 393
## $ species : int 48887
## $ chain : chr "chain:1-393"
## $ referenceGene :'data.frame': 12 obs. of 9 variables:
## $ referenceTranscript:'data.frame': 15 obs. of 9 variables:
## $ className : chr "ReferenceGeneProduct"
## $ schemaClass : chr "ReferenceGeneProduct"Non-Reactome identifiers associated with a ReferenceEntity or PhysicalEntity can be found in these attributes of an instance:
identifierotherIdentifiercrossReferencegeneNamesecondaryIdentifierreferenceGenereferenceTranscript
Event to non-Reactome ids
Non-Reactome identifiers (primaryIdentifier,
secondaryIdentifier, and otherIdentifier) and
gene symbols associated with an Event can also be retrieved by function
event2Ids. Here we try with Reaction “Multiple proteins are
localized at replication fork” (stId R-HSA-176942):
## List of 4
## $ geneSymbol : chr [1:30] "CDC45" "CDC45L" "CDC45L2" "UNQ374/PRO710" ...
## $ primaryIdentifier :'data.frame': 11 obs. of 2 variables:
## ..$ dbId : int [1:11] 86785 176969 356315 67522 99147 94950 94959 94964 94941 94945 ...
## ..$ displayName: chr [1:11] "UniProt:O75419 CDC45" "UniProt:Q9BRT9 GINS4" "UniProt:Q9BRX5 GINS3" "UniProt:Q14691 GINS1" ...
## $ secondaryIdentifier: chr [1:53] "CDC45_HUMAN" "B4DDB4" "B4DDU3" "E9PDH7" ...
## $ otherIdentifier : chr [1:790] "11719699_a_at" "11745049_a_at" "11751123_a_at" "16927052" ...Inferred events
Reactome uses the set of manually curated Human Reactions to computationally infer reactions in fourteen evolutionarily divergent eukaryotic species for which high-quality whole-genome sequence data are available. Therefore a set of high-quality inferred Pathways, Reactions, and PhysicalEntities (proteins) exists in these species. More details about computationally inferred events could be found here.
We can first look at a human pathway “Stabilization of p53” with
identifier R-HSA-69541 and the orthologousEvent slot in its
Reactome Pathway object.
# Look into orthologousEvents of this pathway
stab.p53 <- query("R-HSA-69541")
stab.p53[["orthologousEvent"]]## dbId displayName stId stIdVersion isInDisease
## 1 10032803 Stabilization of p53 R-MMU-69541 R-MMU-69541.1 FALSE
## 2 10153719 Stabilization of p53 R-RNO-69541 R-RNO-69541.1 FALSE
## 3 10260180 Stabilization of p53 R-CFA-69541 R-CFA-69541.1 FALSE
## 4 10372878 Stabilization of p53 R-BTA-69541 R-BTA-69541.1 FALSE
## 5 10487403 Stabilization of p53 R-SSC-69541 R-SSC-69541.1 FALSE
## 6 10549741 Stabilization of p53 R-DRE-69541 R-DRE-69541.1 FALSE
## 7 10623515 Stabilization of p53 R-XTR-69541 R-XTR-69541.1 FALSE
## 8 10721163 Stabilization of p53 R-GGA-69541 R-GGA-69541.1 FALSE
## 9 10807042 Stabilization of p53 R-DME-69541 R-DME-69541.1 FALSE
## 10 10940817 Stabilization of p53 R-DDI-69541 R-DDI-69541.1 FALSE
## 11 10887644 Stabilization of p53 R-CEL-69541 R-CEL-69541.1 FALSE
## isInferred name releaseDate speciesName
## 1 TRUE Stabilization of p53 2024-09-11 Mus musculus
## 2 TRUE Stabilization of p53 2024-09-11 Rattus norvegicus
## 3 TRUE Stabilization of p53 2024-09-11 Canis familiaris
## 4 TRUE Stabilization of p53 2024-09-11 Bos taurus
## 5 TRUE Stabilization of p53 2024-09-11 Sus scrofa
## 6 TRUE Stabilization of p53 2024-09-11 Danio rerio
## 7 TRUE Stabilization of p53 2024-09-11 Xenopus tropicalis
## 8 TRUE Stabilization of p53 2024-09-11 Gallus gallus
## 9 TRUE Stabilization of p53 2024-09-11 Drosophila melanogaster
## 10 TRUE Stabilization of p53 2024-09-11 Dictyostelium discoideum
## 11 TRUE Stabilization of p53 2024-09-11 Caenorhabditis elegans
## inferredFrom
## 1 69541
## 2 69541
## 3 69541
## 4 69541
## 5 69541
## 6 69541
## 7 69541
## 8 69541
## 9 69541
## 10 69541
## 11 69541
## species
## 1 48892, Mus musculus, Mus musculus, M. musculus, Mm, house mouse, 10090, MMU, Species, Species
## 2 48895, Rattus norvegicus, Rattus norvegicus, R. norvegicus, Rn, brown rat, Norway rat, 10116, RNO, Species, Species
## 3 49646, Canis familiaris, Canis familiaris, Canis lupus familiaris, 9615, CFA, Species, Species
## 4 48898, Bos taurus, Bos taurus, B. taurus, Bt, bovine, cattle, cow, domestic cattle, domestic cow, 9913, BTA, Species, Species
## 5 49633, Sus scrofa, Sus scrofa, pig, swine, 9823, SSC, Species, Species
## 6 68323, Danio rerio, Danio rerio, D.rerio, D. rerio, Dr, Brachydanio rerio, zebrafish, zebra fish, 7955, DRE, Species, Species
## 7 205621, Xenopus tropicalis, Xenopus tropicalis, Western clawed frog, Silurana tropicalis, 8364, XTR, Species, Species
## 8 49591, Gallus gallus, Gallus gallus, chicken, 9031, GGA, Species, Species
## 9 56210, Drosophila melanogaster, Drosophila melanogaster, D. melanogaster, Dm, fruit fly, 7227, DME, Species, Species
## 10 170941, Dictyostelium discoideum, Dictyostelium discoideum, 44689, DDI, Species, Species
## 11 68320, Caenorhabditis elegans, Caenorhabditis elegans, C.elegans, C. elegans, Ce, 6239, CEL, Species, Species
## hasDiagram hasEHLD schemaClass className
## 1 FALSE FALSE Pathway Pathway
## 2 FALSE FALSE Pathway Pathway
## 3 FALSE FALSE Pathway Pathway
## 4 FALSE FALSE Pathway Pathway
## 5 FALSE FALSE Pathway Pathway
## 6 FALSE FALSE Pathway Pathway
## 7 FALSE FALSE Pathway Pathway
## 8 FALSE FALSE Pathway Pathway
## 9 FALSE FALSE Pathway Pathway
## 10 FALSE FALSE Pathway Pathway
## 11 FALSE FALSE Pathway PathwayNote that the isInferred value of this human instance is
FALSE, while those of all its orthologous Events in other
species are TRUE.
## [1] FALSEConversely, if you have a non-Human Event or PhysicalEntity instance
and want to get all its orthologies in other species, you could use
function getOrthology to fetch the Human
orthologous instance first, then repeat the steps above:
querythe result identifier- extract those in
orthologousEventattribute
## Returning inferred instances of 'R-SSC-69541' in species 'Homo sapiens'...## $dbId
## [1] 69541
##
## $displayName
## [1] "Stabilization of p53"
##
## $stId
## [1] "R-HSA-69541"
##
## $stIdVersion
## [1] "R-HSA-69541.7"
##
## $isInDisease
## [1] FALSE
##
## $isInferred
## [1] FALSE
##
## $name
## [1] "Stabilization of p53"
##
## $releaseDate
## [1] "2004-07-06"
##
## $speciesName
## [1] "Homo sapiens"
##
## $hasDiagram
## [1] FALSE
##
## $hasEHLD
## [1] FALSE
##
## $lastUpdatedDate
## [1] "2017-04-20"
##
## $schemaClass
## [1] "Pathway"
##
## $className
## [1] "Pathway"Others
Diagram exporter
The Reactome diagram exporter has been mentioned a little bit in ‘Instances in Reactions’ section, here we can reconstruct a few more examples.
What’s more, Reactome offers a pathway Analysis Service that supports enrichment and expression analysis. The diagram exporter allows you to overlay the results of the analysis on top of the exported diagrams. To do so, use the token argument to specify the unique token associated with the performed analysis.
The ReactomeGSA package is an R client to the web-based Reactome Analysis Service, so we could perform analysis in R then access the token.
# Install GSA packages
# devtools::install_github("reactome/ReactomeGSA")
# devtools::install_github("reactome/ReactomeGSA.data")
library(ReactomeGSA)
library(ReactomeGSA.data)
data("griss_melanoma_proteomics")
# Create an analysis request and set parameters
my_request <- ReactomeAnalysisRequest(method = "Camera")
my_request <- set_parameters(request = my_request, max_missing_values = 0.5)
my_request <- add_dataset(request = my_request,
expression_values = griss_melanoma_proteomics,
name = "Proteomics",
type = "proteomics_int",
comparison_factor = "condition",
comparison_group_1 = "MOCK",
comparison_group_2 = "MCM",
additional_factors = c("cell.type", "patient.id"))
# Run analysis
result <- perform_reactome_analysis(request = my_request, compress = F)
# Retrieve the fold-change data for the proteomics dataset
proteomics_fc <- get_result(result, type = "fold_changes", name = "Proteomics")
# Merge the pathway level data for all result sets
combined_pathways <- pathways(result)
# Get the analysis token
token <- gsub(".*=", "", result@reactome_links[[1]][["url"]])
# select the id of the pathway with highest foldchange
id <- rownames(combined_pathways[1,])We could now directly get the diagram in R:
The output image can also saved into a file, details see
?exportImage.
Further, fireworks - the overview of genome-wide, hierarchical visualization of all Reactome pathways - can be exported:
# Fireworks of Human Pathways
exportImage(species = "9606", output = "fireworks", format = "jpg",
token = token, fireworksCoverage = TRUE, quality = 7)
Full event hierarchy for any given main species in Reactome could be
retrieved by function getEventsHierarchy, usage sees
?getEventsHierarchy.
Event file exporter
Reacome is also able to export Events in SBGN or SBML format besides the
pathway diagrams. exportEventFile could retrieve the
content in specified format and save into a file. More details see
?exportEventFile.
Species in Reactome
The list of all species in Reactome Database could be retrieved by
function getSpecies. Moreover, you can specify
main = TRUE to obtain the list of main
species, those have either manually curated or computationally
inferred pathways.
## dbId displayName
## 1 48887 Homo sapiens
## 2 48898 Bos taurus
## 3 68320 Caenorhabditis elegans
## 4 49646 Canis familiaris
## 5 68323 Danio rerio
## 6 170941 Dictyostelium discoideum
## 7 56210 Drosophila melanogaster
## 8 49591 Gallus gallus
## 9 48892 Mus musculus
## 10 176806 Mycobacterium tuberculosis
## 11 170928 Plasmodium falciparum
## 12 48895 Rattus norvegicus
## 13 68322 Saccharomyces cerevisiae
## 14 68324 Schizosaccharomyces pombe
## 15 49633 Sus scrofa
## 16 205621 Xenopus tropicalis
## name
## 1 Homo sapiens, H. sapiens, Hs, human, man
## 2 Bos taurus, B. taurus, Bt, bovine, cattle, cow, domestic cattle, domestic cow
## 3 Caenorhabditis elegans, C.elegans, C. elegans, Ce
## 4 Canis familiaris, Canis lupus familiaris
## 5 Danio rerio, D.rerio, D. rerio, Dr, Brachydanio rerio, zebrafish, zebra fish
## 6 Dictyostelium discoideum
## 7 Drosophila melanogaster, D. melanogaster, Dm, fruit fly
## 8 Gallus gallus, chicken
## 9 Mus musculus, M. musculus, Mm, house mouse
## 10 Mycobacterium tuberculosis
## 11 Plasmodium falciparum, malaria parasite P. falciparum
## 12 Rattus norvegicus, R. norvegicus, Rn, brown rat, Norway rat
## 13 Saccharomyces cerevisiae, S.cerevisiae, S. cerevisiae, Sc, baker's yeast, brewer's yeast, Saccharomyces cerevisiae (strain RM11-1a), Saccharomyces cerevisiae (strain YJM789)
## 14 Schizosaccharomyces pombe, S.pombe, S. pombe, fission yeast, Sp
## 15 Sus scrofa, pig, swine
## 16 Xenopus tropicalis, Western clawed frog, Silurana tropicalis
## taxId abbreviation className schemaClass
## 1 9606 HSA Species Species
## 2 9913 BTA Species Species
## 3 6239 CEL Species Species
## 4 9615 CFA Species Species
## 5 7955 DRE Species Species
## 6 44689 DDI Species Species
## 7 7227 DME Species Species
## 8 9031 GGA Species Species
## 9 10090 MMU Species Species
## 10 1773 MTU Species Species
## 11 5833 PFA Species Species
## 12 10116 RNO Species Species
## 13 4932 SCE Species Species
## 14 4896 SPO Species Species
## 15 9823 SSC Species Species
## 16 8364 XTR Species SpeciesPerson in Reactome
The function getPerson will return information of a
person in Reactome. All attributes in a Person object see here. For
instance, to find information about Justin Cook:
## Matching "Justin Cook" with names in current data...## $dbId
## [1] 9617639
##
## $displayName
## [1] "Cook, J"
##
## $firstname
## [1] "Justin"
##
## $initial
## [1] "J"
##
## $project
## [1] "Reactome"
##
## $surname
## [1] "Cook"
##
## $affiliation
## dbId displayName address
## 1 1169271 Ontario Institute for Cancer Research Toronto ON Canada
## name className schemaClass
## 1 Ontario Institute for Cancer Research, OICR Affiliation Affiliation
##
## $className
## [1] "Person"
##
## $schemaClass
## [1] "Person"Citation
If you found this package useful and used in your projects, please cite it.
## To cite package 'ReactomeContentService4R' in publications use:
##
## Poon C, Cook J, Shorser S, Weiser J, Haw R, Stein L (2021). _R
## interface to the reactome graph database_, volume 10.
## doi:10.7490/f1000research.1118690.1
## <https://doi.org/10.7490/f1000research.1118690.1>.
##
## A BibTeX entry for LaTeX users is
##
## @Manual{,
## author = {Chi-Lam Poon and Justin Cook and Solomon Shorser and Joel Weiser and Robin Haw and Lincoln Stein},
## title = {R interface to the reactome graph database},
## journal = {F1000Research},
## volume = {10},
## pages = {721 (poster)},
## year = {2021},
## doi = {10.7490/f1000research.1118690.1},
## }Session info
## R version 4.4.1 (2024-06-14)
## Platform: x86_64-pc-linux-gnu
## Running under: Ubuntu 24.04.1 LTS
##
## Matrix products: default
## BLAS: /usr/lib/x86_64-linux-gnu/openblas-pthread/libblas.so.3
## LAPACK: /usr/lib/x86_64-linux-gnu/openblas-pthread/libopenblasp-r0.3.26.so; LAPACK version 3.12.0
##
## locale:
## [1] LC_CTYPE=en_US.UTF-8 LC_NUMERIC=C
## [3] LC_TIME=en_US.UTF-8 LC_COLLATE=C
## [5] LC_MONETARY=en_US.UTF-8 LC_MESSAGES=en_US.UTF-8
## [7] LC_PAPER=en_US.UTF-8 LC_NAME=C
## [9] LC_ADDRESS=C LC_TELEPHONE=C
## [11] LC_MEASUREMENT=en_US.UTF-8 LC_IDENTIFICATION=C
##
## time zone: Etc/UTC
## tzcode source: system (glibc)
##
## attached base packages:
## [1] stats graphics grDevices utils datasets methods base
##
## other attached packages:
## [1] ReactomeContentService4R_1.15.0 rmarkdown_2.28
##
## loaded via a namespace (and not attached):
## [1] doParallel_1.0.17 httr_1.4.7 cli_3.6.3 knitr_1.48
## [5] rlang_1.1.4 magick_2.8.5 xfun_0.48 highr_0.11
## [9] jsonlite_1.8.9 data.table_1.16.2 buildtools_1.0.0 htmltools_0.5.8.1
## [13] maketools_1.3.1 sys_3.4.3 sass_0.4.9 evaluate_1.0.1
## [17] jquerylib_0.1.4 fastmap_1.2.0 yaml_2.3.10 foreach_1.5.2
## [21] lifecycle_1.0.4 compiler_4.4.1 codetools_0.2-20 Rcpp_1.0.13
## [25] digest_0.6.37 R6_2.5.1 curl_5.2.3 parallel_4.4.1
## [29] magrittr_2.0.3 bslib_0.8.0 tools_4.4.1 iterators_1.0.14
## [33] cachem_1.1.0