FGFR4 is a single-pass type I transmembrane receptor tyrosine kinase of the fibroblast growth factor receptor family, with three extracellular immunoglobulin-like domains and a split intracellular tyrosine kinase domain. Unlike FGFR1-3 it lacks the IIIb/IIIc alternative exon pair and has a single c-type-like ligand-binding domain; a soluble secreted splice form also exists. FGFR4 binds several paracrine FGFs in a heparan sulfate-dependent manner and is the principal receptor for the endocrine hormone FGF19 (FGF15 in mouse), which it binds together with the coreceptor beta-Klotho (KLB) and sulfated glycosaminoglycans. Ligand-induced dimerization triggers trans-autophosphorylation and phosphorylation of FRS2 and PLCG1, activating RAS-MAPK/ERK1/2, PI3K-AKT, PLC-gamma and STAT3 outputs. Its best-defined physiological role is in hepatocytes, where intestinal FGF19 acting through the KLB-FGFR4 complex and ERK1/2 represses CYP7A1 and thereby bile acid synthesis, forming the enterohepatic feedback loop that maintains bile acid and cholesterol homeostasis. FGFR4 also contributes to FGF19-driven hepatocyte proliferation and liver regeneration. Only fully N-glycosylated FGFR4 reaches the cell surface; after endocytosis a larger fraction of FGFR4 recycles to the plasma membrane than for FGFR1-3, although it is still subject to ligand- and partner-dependent degradation. The common G388R polymorphism stabilizes the receptor and is associated with cancer progression, and FGF19-FGFR4 signaling is an oncogenic driver in a subset of hepatocellular carcinomas.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro kinase-domain mapping to protein kinase activity. FGFR4 is a catalytically active receptor tyrosine kinase. Reason: Correct but broad; the more precise tyrosine kinase and FGF receptor activity terms are also annotated. Broad IEA mappings are acceptable. Supporting Evidence: PMID:18670643 This site is phosphorylated in response to ligand binding and is essential for FGF receptor activity |
| GO:0004713 protein tyrosine kinase activity | EXP PMID:18670643 Altered fibroblast growth factor receptor 4 stability promot... | ACCEPT | Summary: Wang et al. 2008 show ligand-induced phosphorylation of the conserved activation-loop tyrosines of FGFR4 (Tyr642/643) and sustained activation of the Arg388 variant. Reason: Tyrosine kinase activity is intrinsic to FGFR4 and is the enzymatic basis of its receptor function; the EXP annotation is well supported. Supporting Evidence: PMID:18670643 This site is phosphorylated in response to ligand binding and is essential for FGF receptor activity |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (InterPro tyrosine kinase signature, Rhea protein tyrosine phosphorylation reaction). Reason: Consistent with experimental evidence of FGFR4 autophosphorylation and substrate phosphorylation. Supporting Evidence: PMID:18670643 This site is phosphorylated in response to ligand binding and is essential for FGF receptor activity |
| GO:0004714 transmembrane receptor protein tyrosine kinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC 2.7.10.1 mapping to transmembrane receptor protein tyrosine kinase activity. Reason: FGFR4 is a single-pass transmembrane receptor tyrosine kinase; this term is the direct parent of fibroblast growth factor receptor activity. Supporting Evidence: PMID:12815072 a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase |
| GO:0005007 fibroblast growth factor receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBD at the deuterostome FGFR clade node (PTN000699279), seeded by FGFR1-4 and vertebrate orthologs; FGFR4 contributes its own experimental evidence. Reason: Fibroblast growth factor receptor activity is the core molecular function of FGFR4. FGFR4 sits inside the clade that inherited the function and there is no evidence of loss; the node placement is sound. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0005007 fibroblast growth factor receptor activity | IDA PMID:18480409 Ubiquitination of fibroblast growth factor receptor 1 is req... | ACCEPT | Summary: Haugsten et al. 2008 (abstract-only in cache) focuses on FGFR1 ubiquitination and sorting; UniProt cites the paper for FGFR4 catalytic activity and ubiquitination, so FGFR4 was presumably assayed in the full text. Reason: Full text not available here, but the function is clearly correct for FGFR4 and is independently supported; defer to the curator. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. PMID:18670643 This site is phosphorylated in response to ligand binding and is essential for FGF receptor activity |
| GO:0005007 fibroblast growth factor receptor activity | IDA PMID:21653700 Sulfated glycosaminoglycans are required for specific and se... | ACCEPT | Summary: Wu et al. 2011 show FGF19 induces DNA synthesis and ERK activation via human FGFR4 in engineered BaF3 cells, dependent on KLB and sulfated GAGs. Reason: Direct evidence that FGFR4 transduces FGF19 binding into intracellular signaling. Supporting Evidence: PMID:21653700 Here we report that hFGF19 at picomolar levels require sulfated glycosaminoglycans (sGAGs), such as heparan sulfate, heparin, and chondroitin sulfates, for its signaling via human FGFR4 in the presence of human betaKlotho. PMID:21653700 hFGF19 at 1.4, 4, and 12 n m was able to induce DNA synthesis via hFGFR4 only when the receptor was co-expressed with hKLB |
| GO:0005007 fibroblast growth factor receptor activity | IDA PMID:8663044 Receptor specificity of the fibroblast growth factor family. | ACCEPT | Summary: Ornitz et al. 1996 BaF3 mitogenic assays of FGF ligands on cells expressing each FGFR including FGFR4. Reason: Classic ligand-specificity study establishing FGFR4 as a functional FGF receptor (abstract-only in cache; consistent with UniProt). Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. PMID:8663044 These studies demonstrate that FGF 1 is the only FGF that can activate all FGF receptor splice variants. |
| GO:0005007 fibroblast growth factor receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (ARBA, InterPro FGFR family signature). Reason: Fibroblast growth factor receptor activity is the core molecular function of FGFR4. Supporting Evidence: PMID:12815072 a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase |
| GO:0005007 fibroblast growth factor receptor activity | IGI PMID:10525310 FGF-19, a novel fibroblast growth factor with unique specifi... | ACCEPT | Summary: Xie et al. 1999 identify FGF19 as a high-affinity, heparin-dependent ligand exclusive for FGFR4. Reason: FGF19-FGFR4 is the physiologically defining ligand-receptor pair for FGFR4. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. |
| GO:0005007 fibroblast growth factor receptor activity | TAS PMID:10918587 Transformation and Stat activation by derivatives of FGFR1, ... | ACCEPT | Summary: Hart et al. 2000 compare activated (TDII-like) FGFR1, FGFR3 and FGFR4 kinase derivatives, showing shared downstream effectors. Reason: Traceable author statement consistent with FGFR4 receptor activity; the constructs are myristoylated kinase domains, so this is supportive rather than direct ligand-receptor evidence. Supporting Evidence: PMID:10918587 This also represents the first demonstration that activation of FGFR4, in addition to FGFR1 and FGFR3, can induce cellular transformation. PMID:10918587 Phosphorylation of Shp2, PLC-gamma, and MAPK was also stimulated by all three 'TDII-like' FGFR derivatives. |
| GO:0005515 protein binding | IPI PMID:17627937 Liver-specific activities of FGF19 require Klotho beta. | REMOVE | Summary: FGFR4 binds beta-Klotho (KLB, Q86Z14); KLB is the obligate coreceptor for FGF19 binding and signaling through FGFR4. Reason: Generic protein binding is uninformative. Removal does not deny the reported interaction; the functionally meaningful content is captured by more specific annotations where they exist. The FGFR4-KLB interaction is captured functionally by FGF binding, FGFR activity and KLB coreceptor activity (GO:0015026 on KLB). Supporting Evidence: PMID:17627937 KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. |
| GO:0005515 protein binding | IPI PMID:20798051 FGF receptor-4 (FGFR4) polymorphism acts as an activity swit... | REMOVE | Summary: FGFR4 coimmunoprecipitates with MT1-MMP (MMP14, P50281); the complex is allele-dependent (R388 vs G388). Reason: Generic protein binding is uninformative. Removal does not deny the reported interaction; the functionally meaningful content is captured by more specific annotations where they exist. No specific MF term describes this regulatory complex; consequences are captured by the non-core process annotations from this paper. Supporting Evidence: PMID:20798051 The FGFR4-R388 allele, linked to poor cancer prognosis, increased collagen invasion by decreasing lysosomal MT1-MMP degradation. |
| GO:0005515 protein binding | IPI PMID:35384245 Physical and functional interactome atlas of human receptor ... | REMOVE | Summary: High-throughput RTK interactome screen (Salokas et al. 2022) reporting FGFR4 interactions (RET, FGFR1). Reason: Generic protein binding is uninformative. Removal does not deny the reported interaction; the functionally meaningful content is captured by more specific annotations where they exist. Screen-derived binary interactions carry no functional information for FGFR4. |
| GO:0005515 protein binding | IPI PMID:35384245 Physical and functional interactome atlas of human receptor ... | REMOVE | Summary: High-throughput RTK interactome screen (Salokas et al. 2022) reporting FGFR4 interactions (RET, FGFR1). Reason: Generic protein binding is uninformative. Removal does not deny the reported interaction; the functionally meaningful content is captured by more specific annotations where they exist. Screen-derived binary interactions carry no functional information for FGFR4. |
| GO:0005515 protein binding | IPI PMID:35922511 A physical wiring diagram for the human immune system. | REMOVE | Summary: High-throughput immune-cell surface interactome screen (Shilts et al. 2022) reporting FGFR4 binding to SDC2 and TGFBR3. Reason: Generic protein binding is uninformative. Removal does not deny the reported interaction; the functionally meaningful content is captured by more specific annotations where they exist. SDC2 and TGFBR3 are heparan sulfate proteoglycans, consistent with known HS-dependence of FGF-FGFR complexes, but a generic protein binding term adds nothing. |
| GO:0005515 protein binding | IPI PMID:35922511 A physical wiring diagram for the human immune system. | REMOVE | Summary: High-throughput immune-cell surface interactome screen (Shilts et al. 2022) reporting FGFR4 binding to SDC2 and TGFBR3. Reason: Generic protein binding is uninformative. Removal does not deny the reported interaction; the functionally meaningful content is captured by more specific annotations where they exist. SDC2 and TGFBR3 are heparan sulfate proteoglycans, consistent with known HS-dependence of FGF-FGFR complexes, but a generic protein binding term adds nothing. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro kinase ATP-binding site mapping. Reason: ATP binding is required for tyrosine kinase catalysis; mechanistically correct though not informative on its own. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location 'Secreted' mapping, derived from soluble isoform 2 (P22455-2). Reason: Applies only to the soluble splice form lacking the transmembrane region; the canonical receptor is a plasma membrane protein. |
| GO:0005768 endosome | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location 'Endosome'. FGFR4 is internalised by clathrin-mediated endocytosis and trafficked through endosomes, with a substantial recycling fraction. Reason: Endosomal localisation is well documented for FGFR4 and is functionally relevant (sustained signalling, recycling). Supporting Evidence: file:human/FGFR4/FGFR4-deep-research-falcon.md This recycling route, mediated by Rab11, returns FGFR4 to the plasma membrane and is associated with sustained signaling |
| GO:0005783 endoplasmic reticulum | IDA PMID:20683963 Glycosylation of fibroblast growth factor receptor 4 is a ke... | KEEP AS NON CORE | Summary: Triantis et al. 2010: core-glycosylated FGFR4 is bound by ER-resident beta-Klotho and directed to the proteasome; only the terminally glycosylated form reaches the surface. Reason: ER localisation reflects the biosynthetic (immature) pool, relevant to quality control of the receptor, not the site of signaling. ORGANELLES check (2026-11-05): FGFR4 is a single-pass type I plasma-membrane receptor tyrosine kinase with a cleaved signal peptide and no ER retention motif, so the ER is transit, not residence. The row is kept as non-core rather than marked over-annotated because the evidence is direct and on the gene itself (the core-glycosylated glycoform is bound by ER-resident beta-Klotho and sent to the proteasome, while only the terminal glycoform reaches the surface); the cached record is abstract-only and does not say whether the ER assays used endogenous or transfected FGFR4, so the curator's full-text reading is deferred to. MARK_AS_OVER_ANNOTATED would be the alternative if the ER pool proved to be retention of overexpressed receptor. No ER membrane term is added, since a transit pool does not establish residence (ER batch 1 rule, as for ABCA4 and BACE2). Supporting Evidence: PMID:20683963 We show here that beta-Klotho is an endoplasmic reticulum-resident protein that affects the cellular abundance of different FGFR4 glycoforms. PMID:20683963 beta-Klotho binds and directs the core glycoform of FGFR4 to the proteasome, and it allows only a terminal glycoform to reach the plasma membrane. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location 'Endoplasmic reticulum' mapping. Reason: Biosynthetic ER pool; see the IDA from PMID:20683963. ORGANELLES check (2026-11-05): the SL-0095 mapping comes from the UniProt location "Endoplasmic reticulum", which carries no evidence tag in the record and matches the curated IDA from PMID:20683963 (core-glycosylated FGFR4 held by beta-Klotho in the ER). It carries the same transit claim as the IDA row and is kept as non-core at the root; FGFR4 has no retention motif, so no ER membrane term is added. Supporting Evidence: PMID:20683963 beta-Klotho binds and directs the core glycoform of FGFR4 to the proteasome, and it allows only a terminal glycoform to reach the plasma membrane. |
| GO:0005794 Golgi apparatus | IDA PMID:18061161 The cell surface receptor FGFRL1 forms constitutive dimers t... | KEEP AS NON CORE | Summary: Rieckmann et al. 2008 is a study of FGFRL1 (abstract-only in cache); the abstract does not mention FGFR4, which was presumably used as a comparator in the full text. Reason: Cannot see the curator's evidence, so not removed. Golgi localisation of immature FGFR4 is independently supported (Canete et al. 2007) and matches glycan maturation, but it is a transit compartment, not the site of core function. Supporting Evidence: PMID:17311277 FGF-independent activation of STAT1 was demonstrated at the Golgi apparatus where it was colocalized with FGFRs. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBD at the receptor tyrosine kinase node PTN001230349. Reason: FGFR4 is a plasma membrane receptor; node placement is sound. Supporting Evidence: PMID:20683963 beta-Klotho binds and directs the core glycoform of FGFR4 to the proteasome, and it allows only a terminal glycoform to reach the plasma membrane. |
| GO:0005886 plasma membrane | IDA PMID:18061161 The cell surface receptor FGFRL1 forms constitutive dimers t... | ACCEPT | Summary: IDA from an FGFRL1 paper (abstract-only); FGFR4 presumably examined in the full text. Reason: Plasma membrane localisation of FGFR4 is certain and independently documented (e.g. PMID:20683963); defer to the curator. Supporting Evidence: PMID:20683963 beta-Klotho binds and directs the core glycoform of FGFR4 to the proteasome, and it allows only a terminal glycoform to reach the plasma membrane. |
| GO:0005886 plasma membrane | IDA PMID:20683963 Glycosylation of fibroblast growth factor receptor 4 is a ke... | ACCEPT | Summary: Fully glycosylated FGFR4 reaches the plasma membrane, where it is phosphorylated in response to FGF19. Reason: Direct support for the functional cell-surface pool. Supporting Evidence: PMID:20683963 beta-Klotho binds and directs the core glycoform of FGFR4 to the proteasome, and it allows only a terminal glycoform to reach the plasma membrane. PMID:20683963 Only the terminal FGFR4 glycoform is phosphorylated upon FGF19 treatment of HepG2 cells, and this shows that only fully glycosylated FGFR4 is active in CYP7A1 down-regulation. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location 'Cell membrane' mapping. Reason: Correct for the transmembrane receptor. |
| GO:0005886 plasma membrane | TAS PMID:10918587 Transformation and Stat activation by derivatives of FGFR1, ... | ACCEPT | Summary: Hart et al. 2000 targeted activated FGFR kinase derivatives to the plasma membrane via a myristylation signal. Reason: Plasma membrane is the site of FGFR4 signaling; the TAS is consistent with established knowledge. Supporting Evidence: PMID:10918587 This also represents the first demonstration that activation of FGFR4, in addition to FGFR1 and FGFR3, can induce cellular transformation. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-109699 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1307955 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1307963 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-190265 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-190326 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2012086 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2012087 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2038944 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2038946 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2046363 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2316434 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2400009 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654151 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654163 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654169 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654418 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654422 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654423 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654425 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654426 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654428 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654566 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654651 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654653 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654655 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654658 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654659 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654662 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654663 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654664 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654667 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654669 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654684 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654714 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654717 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654734 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655235 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655248 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655252 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655284 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655313 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655336 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655341 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655347 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655348 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655351 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5672965 | ACCEPT | Summary: Reactome reaction placing FGFR4 (ligand-bound, activated or mutant forms) at the plasma membrane in FGFR4 signaling events. Reason: FGFR4 is a plasma membrane receptor tyrosine kinase and Reactome FGFR4 reactions occur at the plasma membrane; the TAS is correct. |
| GO:0005911 cell-cell junction | IDA PMID:20798051 FGF receptor-4 (FGFR4) polymorphism acts as an activity swit... | KEEP AS NON CORE | Summary: Endogenous FGFR4-R388 localised to cell-cell junctions in MDA-MB-453 breast cancer cells (colocalizes_with). Reason: Observed for the risk allele in a cancer line; consistent with FGFR4 association with N-cadherin/NCAM complexes, but a context-specific sub-location. Supporting Evidence: PMID:20798051 Accordingly, the endogenous FGFR4-R388 risk allele was localized to the cellβcell junctions in MDA-MB-453 cells. |
| GO:0008201 heparin binding | IDA PMID:18480409 Ubiquitination of fibroblast growth factor receptor 1 is req... | ACCEPT | Summary: Heparin binding by FGFR4 (abstract-only paper centred on FGFR1). Reason: FGFRs contain a heparin/heparan sulfate binding site in D2 that is part of the FGF-HS-FGFR ternary complex, and FGF19 signaling via FGFR4 depends on sulfated GAGs; function is clearly correct, so defer to the curator. Supporting Evidence: PMID:21653700 Here we report that hFGF19 at picomolar levels require sulfated glycosaminoglycans (sGAGs), such as heparan sulfate, heparin, and chondroitin sulfates, for its signaling via human FGFR4 in the presence of human betaKlotho. |
| GO:0008284 positive regulation of cell population proliferation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT IBD at the eumetazoan FGFR node PTN004704281. Reason: Node placement is sound (FGFR4 inherits this from the FGFR clade). FGFR4 activation drives proliferation in engineered BaF3 cells and FGF19-driven hepatocyte proliferation in vivo, but proliferation is a context-dependent downstream outcome of FGFR signaling rather than the defining role of FGFR4 (which is hepatic endocrine metabolic signaling). Supporting Evidence: PMID:20018895 These data suggest that activation of FGFR4 is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation. |
| GO:0008284 positive regulation of cell population proliferation | IDA PMID:8663044 Receptor specificity of the fibroblast growth factor family. | KEEP AS NON CORE | Summary: Mitogenic response of BaF3 cells expressing FGFR4 to FGF ligands. Reason: FGFR4 activation drives proliferation in engineered BaF3 cells and FGF19-driven hepatocyte proliferation in vivo, but proliferation is a context-dependent downstream outcome of FGFR signaling rather than the defining role of FGFR4 (which is hepatic endocrine metabolic signaling). Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008284 positive regulation of cell population proliferation | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined IEA (ARBA, InterPro FGFR family). Reason: FGFR4 activation drives proliferation in engineered BaF3 cells and FGF19-driven hepatocyte proliferation in vivo, but proliferation is a context-dependent downstream outcome of FGFR signaling rather than the defining role of FGFR4 (which is hepatic endocrine metabolic signaling). |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | KEEP AS NON CORE | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) in the Ornitz BaF3 mitogenic assay. Reason: FGFR4 activation drives proliferation in engineered BaF3 cells and FGF19-driven hepatocyte proliferation in vivo, but proliferation is a context-dependent downstream outcome of FGFR signaling rather than the defining role of FGFR4 (which is hepatic endocrine metabolic signaling). Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | KEEP AS NON CORE | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) in the Ornitz BaF3 mitogenic assay. Reason: FGFR4 activation drives proliferation in engineered BaF3 cells and FGF19-driven hepatocyte proliferation in vivo, but proliferation is a context-dependent downstream outcome of FGFR signaling rather than the defining role of FGFR4 (which is hepatic endocrine metabolic signaling). Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | KEEP AS NON CORE | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) in the Ornitz BaF3 mitogenic assay. Reason: FGFR4 activation drives proliferation in engineered BaF3 cells and FGF19-driven hepatocyte proliferation in vivo, but proliferation is a context-dependent downstream outcome of FGFR signaling rather than the defining role of FGFR4 (which is hepatic endocrine metabolic signaling). Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | KEEP AS NON CORE | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) in the Ornitz BaF3 mitogenic assay. Reason: FGFR4 activation drives proliferation in engineered BaF3 cells and FGF19-driven hepatocyte proliferation in vivo, but proliferation is a context-dependent downstream outcome of FGFR signaling rather than the defining role of FGFR4 (which is hepatic endocrine metabolic signaling). Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | KEEP AS NON CORE | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) in the Ornitz BaF3 mitogenic assay. Reason: FGFR4 activation drives proliferation in engineered BaF3 cells and FGF19-driven hepatocyte proliferation in vivo, but proliferation is a context-dependent downstream outcome of FGFR signaling rather than the defining role of FGFR4 (which is hepatic endocrine metabolic signaling). Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008284 positive regulation of cell population proliferation | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | KEEP AS NON CORE | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) in the Ornitz BaF3 mitogenic assay. Reason: FGFR4 activation drives proliferation in engineered BaF3 cells and FGF19-driven hepatocyte proliferation in vivo, but proliferation is a context-dependent downstream outcome of FGFR signaling rather than the defining role of FGFR4 (which is hepatic endocrine metabolic signaling). Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBD at the eumetazoan FGFR node PTN004704281. Reason: FGFR4 is a core receptor of the FGF receptor signaling pathway; node placement is sound. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IDA PMID:18480409 Ubiquitination of fibroblast growth factor receptor 1 is req... | ACCEPT | Summary: IDA from an abstract-only paper centred on FGFR1 trafficking; UniProt cites it for FGFR4 activity. Reason: Function clearly correct; defer to the curator. Supporting Evidence: PMID:21653700 Here we report that hFGF19 at picomolar levels require sulfated glycosaminoglycans (sGAGs), such as heparan sulfate, heparin, and chondroitin sulfates, for its signaling via human FGFR4 in the presence of human betaKlotho. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IDA PMID:21653700 Sulfated glycosaminoglycans are required for specific and se... | ACCEPT | Summary: FGF19 signals through FGFR4 (with KLB and sulfated GAGs) to activate ERK and DNA synthesis. Reason: Direct demonstration of FGFR4-mediated FGF signaling. Supporting Evidence: PMID:21653700 Here we report that hFGF19 at picomolar levels require sulfated glycosaminoglycans (sGAGs), such as heparan sulfate, heparin, and chondroitin sulfates, for its signaling via human FGFR4 in the presence of human betaKlotho. PMID:21653700 sGAG-dependent activation of ERK by 30 p m hFGF19 in cells co-expressing hFGFR4 and hKLB was clearly observed in the presence of HS, CS-B, CS-E, or heparin |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro FGFR family mapping. Reason: Correct. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | ACCEPT | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) activating FGFR4-expressing BaF3 cells. Reason: Establishes the ligand repertoire through which FGFR4 signals. Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | ACCEPT | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) activating FGFR4-expressing BaF3 cells. Reason: Establishes the ligand repertoire through which FGFR4 signals. Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | ACCEPT | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) activating FGFR4-expressing BaF3 cells. Reason: Establishes the ligand repertoire through which FGFR4 signals. Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | ACCEPT | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) activating FGFR4-expressing BaF3 cells. Reason: Establishes the ligand repertoire through which FGFR4 signals. Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | ACCEPT | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) activating FGFR4-expressing BaF3 cells. Reason: Establishes the ligand repertoire through which FGFR4 signals. Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IGI PMID:8663044 Receptor specificity of the fibroblast growth factor family. | ACCEPT | Summary: IGI with individual FGF ligands (FGF1, FGF2, FGF4, FGF6, FGF8, FGF9) activating FGFR4-expressing BaF3 cells. Reason: Establishes the ligand repertoire through which FGFR4 signals. Supporting Evidence: PMID:8663044 To determine potentially relevant ligand-receptor pairs we have engineered mitogenically responsive cell lines expressing the major splice variants of all the known FGF receptors. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IPI PMID:10525310 FGF-19, a novel fibroblast growth factor with unique specifi... | ACCEPT | Summary: IPI with FGF19: FGF19 binds FGFR4 with high affinity and exclusivity. Reason: FGF19-FGFR4 binding is the entry point of FGFR4 signaling. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | TAS PMID:10918587 Transformation and Stat activation by derivatives of FGFR1, ... | ACCEPT | Summary: Activated FGFR4 kinase derivatives stimulate SHP2, PLC-gamma, MAPK, STAT and PI3K signaling. Reason: Consistent with FGFR4 transducing canonical FGFR outputs. Supporting Evidence: PMID:10918587 Phosphorylation of Shp2, PLC-gamma, and MAPK was also stimulated by all three 'TDII-like' FGFR derivatives. |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning prediction of regulation of gene expression. Reason: Vague but not wrong: FGFR4 signaling represses CYP7A1 transcription. The informative process is negative regulation of bile acid biosynthesis. Supporting Evidence: PMID:17623664 FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. |
| GO:0010628 positive regulation of gene expression | IMP PMID:19085950 Bile acids activate fibroblast growth factor 19 signaling in... | MODIFY | Summary: Song et al. 2009 (full text): FGFR4 siRNA in HepG2 cells reduced FXR-agonist (GW4064)-mediated repression of CYP7A1 mRNA by 50%. Reason: The only FGFR4 loss-of-function result in this paper shows FGFR4 is needed to REPRESS CYP7A1 expression, i.e. negative, not positive, regulation of gene expression. The direction of the annotation appears inverted; negative regulation of gene expression matches the data (and negative regulation of bile acid biosynthesis is the physiological process). Proposed replacements: negative regulation of gene expression Supporting Evidence: PMID:19085950 siRNA knockdown of FGFR4 (siFGFR4) reduced FGFR4 protein and mRNA expression in HepG2 cells (Fig. 6B and Fig. 6C), and resulted in 50% reduction of GW4064-mediated repression of CYP7A1 mRNA expression compared to control siRNA (Fig. 6D) |
| GO:0010715 regulation of extracellular matrix disassembly | IMP PMID:20876804 Fibroblast growth factor receptor 4 regulates tumor invasion... | KEEP AS NON CORE | Summary: Sugiyama et al. 2010 (abstract-only): knockdown of the FGFR4-R388 risk allele reduced MT1-MMP-dependent collagen invasion; knockdown of the G388 allele had the opposite effect. Reason: Allele-dependent effect on MT1-MMP-mediated matrix degradation in carcinoma cells; real but not a core, physiological FGFR4 function. Supporting Evidence: PMID:20876804 knockdown of FGFR4-R388 or MT1-MMP by RNA interference blocked tumor cell invasion and growth in collagen |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro mapping to membrane. Reason: Correct though less specific than plasma membrane. |
| GO:0016477 cell migration | IMP PMID:20876804 Fibroblast growth factor receptor 4 regulates tumor invasion... | KEEP AS NON CORE | Summary: FGFR4-R388 knockdown blocked tumor-cell invasion in 3D collagen. Reason: Cancer-cell invasion phenotype, allele-dependent; plausible downstream consequence of FGFR signaling but not core. Supporting Evidence: PMID:20876804 knockdown of FGFR4-R388 or MT1-MMP by RNA interference blocked tumor cell invasion and growth in collagen |
| GO:0017134 fibroblast growth factor binding | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBD at the deuterostome FGFR clade node PTN000699279. Reason: FGF binding is the ligand-recognition component of FGFR4 function. Node placement sound. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. |
| GO:0017134 fibroblast growth factor binding | IDA PMID:18480409 Ubiquitination of fibroblast growth factor receptor 1 is req... | ACCEPT | Summary: IDA from abstract-only FGFR1-focused paper; FGFR4 presumably assayed in full text. Reason: FGF binding is the ligand-recognition component of FGFR4 function. Function clearly correct; defer to curator. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. |
| GO:0017134 fibroblast growth factor binding | IDA PMID:8663044 Receptor specificity of the fibroblast growth factor family. | ACCEPT | Summary: FGF ligand activation of FGFR4-expressing BaF3 cells. Reason: FGF binding is the ligand-recognition component of FGFR4 function. Supporting Evidence: PMID:8663044 These studies demonstrate that FGF 1 is the only FGF that can activate all FGF receptor splice variants. |
| GO:0017134 fibroblast growth factor binding | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction. Reason: FGF binding is the ligand-recognition component of FGFR4 function. |
| GO:0017134 fibroblast growth factor binding | IPI PMID:10525310 FGF-19, a novel fibroblast growth factor with unique specifi... | ACCEPT | Summary: FGF19 binds FGFR4 with high affinity and exclusivity. Reason: FGF binding is the ligand-recognition component of FGFR4 function. Supporting Evidence: PMID:10525310 FGF-19 is a high affinity, heparin dependent ligand for FGFR4 and is the first member of the FGF family to show exclusive binding to FGFR4. |
| GO:0017134 fibroblast growth factor binding | IPI PMID:17627937 Liver-specific activities of FGF19 require Klotho beta. | ACCEPT | Summary: FGF19 binding to FGFR4 requires KLB. Reason: FGF binding is the ligand-recognition component of FGFR4 function. Endocrine FGF19 binding depends on the KLB coreceptor. Supporting Evidence: PMID:17627937 KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. |
| GO:0018108 peptidyl-tyrosine phosphorylation | IDA PMID:20683963 Glycosylation of fibroblast growth factor receptor 4 is a ke... | ACCEPT | Summary: Terminally glycosylated FGFR4 is tyrosine-phosphorylated upon FGF19 treatment of HepG2 cells. Reason: FGFR4 tyrosine phosphorylation (largely trans-autophosphorylation) is an intrinsic step of its receptor activity. Supporting Evidence: PMID:20683963 Only the terminal FGFR4 glycoform is phosphorylated upon FGF19 treatment of HepG2 cells, and this shows that only fully glycosylated FGFR4 is active in CYP7A1 down-regulation. |
| GO:0019216 regulation of lipid metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Fgfr4 (Q03142) knockout phenotypes. Fgfr4-deficient mice show altered hepatic lipid/cholesterol and bile acid metabolism. Reason: Largely a systemic consequence of FGF15/19-FGFR4 control of bile acid synthesis; plausible for human FGFR4 but indirect. Supporting Evidence: PMID:17623664 Thus, the genetic evidence strongly suggests that FGF15/19, FGFR4, and Ξ² Klotho are essential components in the negative regulation of bile acid synthesis. |
| GO:0030133 transport vesicle | IDA PMID:18061161 The cell surface receptor FGFRL1 forms constitutive dimers t... | UNDECIDED | Summary: IDA from an FGFRL1 paper (abstract-only); the abstract does not mention FGFR4 or transport vesicles for FGFR4. Reason: The supporting evidence for FGFR4 is not visible in the cached abstract and full text could not be retrieved; FGFR4 does traffic through vesicular compartments, but without seeing the data the vesicle identity cannot be judged. |
| GO:0042593 glucose homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Fgfr4 (Q03142) knockout phenotypes. Fgfr4 null mice have metabolic (glucose tolerance) phenotypes. Reason: Organism-level homeostatic phenotype; FGFR4 contributes indirectly via hepatic endocrine FGF signaling. |
| GO:0042632 cholesterol homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Fgfr4 (Q03142) knockout phenotypes. Loss of Fgfr4 raises CYP7A1 and bile acid pool, a major route of cholesterol catabolism. Reason: Consequence of FGFR4 repression of bile acid synthesis from cholesterol; physiologically relevant but downstream of the core process. Supporting Evidence: PMID:12815072 a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase |
| GO:0043085 positive regulation of catalytic activity | IMP PMID:20798051 FGF receptor-4 (FGFR4) polymorphism acts as an activity swit... | MARK AS OVER ANNOTATED | Summary: FGFR4-R388 increases MT1-MMP activity/collagen invasion by decreasing lysosomal MT1-MMP degradation; the G388 allele suppresses MT1-MMP. Reason: The effect is indirect (protein stabilisation, not enzyme activation), allele-dependent (opposite for G388) and the term is very general. Not a core FGFR4 function. Supporting Evidence: PMID:20798051 The FGFR4-R388 allele, linked to poor cancer prognosis, increased collagen invasion by decreasing lysosomal MT1-MMP degradation. PMID:20798051 In contrast, the FGFR4-G388 allele suppressed the coexpressed MT1-MMP |
| GO:0043235 signaling receptor complex | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBD at the RTK node PTN001230349. Reason: FGFR4 signals as part of FGF:heparan sulfate:FGFR (and FGF19:KLB:FGFR4) receptor complexes; the node placement is sound. Supporting Evidence: PMID:17627937 KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. |
| GO:0043410 positive regulation of MAPK cascade | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of positive regulation of MAPK cascade. Reason: FGFR4 activates the RAS-MAPK/ERK cascade via FRS2/GRB2/SOS; the more specific ERK1/2 term is also present. Supporting Evidence: PMID:21653700 sGAG-dependent activation of ERK by 30 p m hFGF19 in cells co-expressing hFGFR4 and hKLB was clearly observed in the presence of HS, CS-B, CS-E, or heparin |
| GO:0045862 positive regulation of proteolysis | IMP PMID:20798051 FGF receptor-4 (FGFR4) polymorphism acts as an activity swit... | KEEP AS NON CORE | Summary: FGFR4-G388 promotes down-regulation (lysosomal degradation) of coexpressed MT1-MMP. Reason: Allele- and cell-context-dependent regulation of MT1-MMP turnover in cancer cells; real but not core. Supporting Evidence: PMID:20798051 In contrast, the FGFR4-G388 allele suppressed the coexpressed MT1-MMP |
| GO:0046777 protein autophosphorylation | IDA PMID:20798051 FGF receptor-4 (FGFR4) polymorphism acts as an activity swit... | ACCEPT | Summary: FGFR4 autophosphorylation observed on coexpression with MT1-MMP; enhanced for the R388 allele. Reason: Ligand-induced trans-autophosphorylation is the activation mechanism of FGFR4. Supporting Evidence: PMID:20798051 Coexpression of MT1-MMP with either allele of FGFR4 resulted in MT1-MMP tyrosyl phosphorylation coincidentally with FGFR4 autophosphorylation |
| GO:0055062 phosphate ion homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse Fgfr4 (Q03142) knockout phenotypes. FGFR4 contributes with FGFR1/FGFR3 to FGF23-Klotho signaling controlling phosphate homeostasis. Reason: Minor, redundant contribution relative to FGFR1c-Klotho in kidney; organism-level homeostasis. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBD at the FGFR4-lineage node PTN004704289 (Euteleostomi). Reason: ERK1/2 activation is the principal FGFR4 output, including in hepatocytes where it mediates CYP7A1 repression. FGFR4 appearing in its own WITH/FROM reflects its experimental grounding. Supporting Evidence: PMID:21653700 sGAG-dependent activation of ERK by 30 p m hFGF19 in cells co-expressing hFGFR4 and hKLB was clearly observed in the presence of HS, CS-B, CS-E, or heparin |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IMP PMID:21653700 Sulfated glycosaminoglycans are required for specific and se... | ACCEPT | Summary: FGF19-induced ERK phosphorylation via FGFR4/KLB in BaF3 cells depends on sulfated GAGs. Reason: Direct evidence for FGFR4-driven ERK1/2 activation. Supporting Evidence: PMID:21653700 sGAG-dependent activation of ERK by 30 p m hFGF19 in cells co-expressing hFGFR4 and hKLB was clearly observed in the presence of HS, CS-B, CS-E, or heparin |
| GO:0070857 regulation of bile acid biosynthetic process | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBD at the FGFR4-lineage node PTN004704289, seeded by human FGFR4 and mouse Fgfr4. Reason: FGFR4 is the hepatocyte receptor kinase through which intestinal FGF15/19 (with beta-Klotho) represses CYP7A1 and bile acid synthesis; FGFR4 performs the signal-transducing step, so this is genuine participation. Node placement on the FGFR4 lineage is appropriate. The direction is known (repression), so the generic parent should be replaced by its child GO:0070858. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: negative regulation of bile acid biosynthetic process Supporting Evidence: PMID:17623664 Thus, the genetic evidence strongly suggests that FGF15/19, FGFR4, and Ξ² Klotho are essential components in the negative regulation of bile acid synthesis. |
| GO:0070857 regulation of bile acid biosynthetic process | IEA GO_REF:0000117 | MODIFY | Summary: ARBA prediction. Reason: FGFR4 is the hepatocyte receptor kinase through which intestinal FGF15/19 (with beta-Klotho) represses CYP7A1 and bile acid synthesis; FGFR4 performs the signal-transducing step, so this is genuine participation. The direction is known (repression), so the generic parent should be replaced by its child GO:0070858. Proposed replacements: negative regulation of bile acid biosynthetic process Supporting Evidence: PMID:17623664 Thus, the genetic evidence strongly suggests that FGF15/19, FGFR4, and Ξ² Klotho are essential components in the negative regulation of bile acid synthesis. |
| GO:0070857 regulation of bile acid biosynthetic process | IMP PMID:17623664 Tissue-specific expression of betaKlotho and fibroblast grow... | MODIFY | Summary: Kurosu et al. 2007: FGF19 signals efficiently only through the betaKlotho-FGFR4 complex and represses CYP7A1 in hepatocytes; KLB knockdown attenuates this. Reason: FGFR4 is the hepatocyte receptor kinase through which intestinal FGF15/19 (with beta-Klotho) represses CYP7A1 and bile acid synthesis; FGFR4 performs the signal-transducing step, so this is genuine participation. The evidence is directional (repression), so the generic parent should be replaced by its child GO:0070858 negative regulation of bile acid biosynthetic process. Proposed replacements: negative regulation of bile acid biosynthetic process Supporting Evidence: PMID:17623664 Thus, the genetic evidence strongly suggests that FGF15/19, FGFR4, and Ξ² Klotho are essential components in the negative regulation of bile acid synthesis. PMID:17623664 FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. PMID:19085950 siRNA knockdown of FGFR4 (siFGFR4) reduced FGFR4 protein and mRNA expression in HepG2 cells (Fig. 6B and Fig. 6C), and resulted in 50% reduction of GW4064-mediated repression of CYP7A1 mRNA expression compared to control siRNA (Fig. 6D) |
| GO:0070857 regulation of bile acid biosynthetic process | IMP PMID:20683963 Glycosylation of fibroblast growth factor receptor 4 is a ke... | MODIFY | Summary: Triantis et al. 2010: only fully glycosylated FGFR4 is phosphorylated by FGF19 and active in CYP7A1 down-regulation. Reason: FGFR4 is the hepatocyte receptor kinase through which intestinal FGF15/19 (with beta-Klotho) represses CYP7A1 and bile acid synthesis; FGFR4 performs the signal-transducing step, so this is genuine participation. The observed effect is CYP7A1 down-regulation, so the generic parent should be replaced by its child GO:0070858 negative regulation of bile acid biosynthetic process. Proposed replacements: negative regulation of bile acid biosynthetic process Supporting Evidence: PMID:20683963 Only the terminal FGFR4 glycoform is phosphorylated upon FGF19 treatment of HepG2 cells, and this shows that only fully glycosylated FGFR4 is active in CYP7A1 down-regulation. |
| GO:1903412 response to bile acid | IMP NOT PMID:19085950 Bile acids activate fibroblast growth factor 19 signaling in... | REMOVE | Summary: NOT annotation: FGFR4 not involved in response to bile acid. In Song et al. 2009 (full text), CDCA did not change total FGFR4 protein, but CDCA increased FGFR4 tyrosine phosphorylation and FGFR4 siRNA blunted FXR-agonist repression of CYP7A1. Reason: The only negative result in the paper is that CDCA did not change total FGFR4 protein, which is an expression observation and cannot show that FGFR4 lacks a function; a NOT to a 'response to' process should not rest on an expression or abundance null. A positive 'response to bile acid' annotation would not be right either. The paper states that CDCA is not itself an activator of FGFR4; FGFR4 phosphorylation follows bile-acid induction of FGF19 through FXR, so FGFR4 senses FGF19, not bile acid. That role is captured by negative regulation of bile acid biosynthetic process (GO:0070858). Neither the NOT nor a positive response-to-bile-acid annotation is warranted. Supporting Evidence: PMID:19085950 CDCA treatment (50 ΞΌM) did not alter total FGFR4 protein levels. PMID:19085950 However, an anti-phosphotyrosine antibody detected increased expression of phosphorylated FGFR4 in primary human hepatocytes after CDCA treatment for 24 h PMID:19085950 Since CDCA is not an activator of FGFR4, this result suggests that a FXR/FGF19/FGFR4 auto regulatory loop may exist in human hepatocytes. PMID:19085950 siRNA knockdown of FGFR4 (siFGFR4) reduced FGFR4 protein and mRNA expression in HepG2 cells (Fig. 6B and Fig. 6C), and resulted in 50% reduction of GW4064-mediated repression of CYP7A1 mRNA expression compared to control siRNA (Fig. 6D) |
| GO:2000573 positive regulation of DNA biosynthetic process | IMP PMID:21653700 Sulfated glycosaminoglycans are required for specific and se... | MODIFY | Summary: FGF19 induces DNA synthesis (proliferation readout) in BaF3 cells via FGFR4 with KLB. Reason: DNA synthesis in the BaF3 assay is a mitogenesis/proliferation readout, not regulation of DNA biosynthesis as a metabolic process; the appropriate term is positive regulation of cell population proliferation (non-core). Proposed replacements: positive regulation of cell population proliferation Supporting Evidence: PMID:21653700 hFGF19 at 1.4, 4, and 12 n m was able to induce DNA synthesis via hFGFR4 only when the receptor was co-expressed with hKLB |
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Download this section (compressed HTML)Q: Is the higher recycling of FGFR4 relative to FGFR1-3 observed for FGF19-KLB-FGFR4 complexes in hepatocytes, or only for FGF1-stimulated receptor in transfected cells, and how does the G388R variant alter it?
Q: What does the FGFR4 data in PMID:18061161 (an FGFRL1 paper) actually show that supports the Golgi and transport vesicle annotations?
Q: Should the NOT 'response to bile acid' (GO:1903412) and 'positive regulation of gene expression' (GO:0010628) IMP annotations from PMID:19085950 be re-examined, given that the paper shows FGFR4 is required for bile-acid/FXR-driven repression of CYP7A1?
Q: How much does FGFR4 contribute to FGF23-Klotho phosphate homeostasis in humans relative to FGFR1c and FGFR3c?
Experiment: Compare surface-biotinylation recycling and lysosomal degradation of endogenous FGFR4 in primary human hepatocytes after FGF19 vs FGF1, with Rab11 or ubiquitination-site perturbation, and measure ERK duration and CYP7A1 mRNA.
Hypothesis: FGFR4 sorting to recycling endosomes after FGF19-KLB stimulation sustains ERK signaling and CYP7A1 repression in hepatocytes.
Type: Receptor trafficking and signaling kinetics
Experiment: In FGFR4-knockout human hepatocyte-like cells, re-express wild-type or kinase-dead FGFR4 and measure FGF19-induced FRS2/ERK phosphorylation and CYP7A1 repression.
Hypothesis: The FGF19 response of human hepatocytes requires FGFR4 kinase activity rather than FGFR4 acting only as a KLB scaffold.
Type: Genetic rescue with kinase-dead receptor
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