Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2.
Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway.
Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling
Monomer. Homodimer after ligand binding. Interacts with FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, FGF16, FGF17, FGF18, FGF19, FGF21 and FGF23 (in vitro).
Binding affinity for FGF family members is enhanced by interactions between FGFs and heparan sulfate proteoglycans. Interacts with KLB; this strongly increases the affinity for FGF19 and FGF23. Affinity for FGF19 is strongly increased by KLB and sulfated glycosaminoglycans.
KLB and KL both interact with the core-glycosylated FGFR4 in the endoplasmic reticulum and promote its degradation, so that only FGFR4 with fully mature N-glycans is expressed at the cell surface. Identified in a complex with NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Interacts with MMP14 and HIP1 (PubMed:11433297, PubMed:16597617, PubMed:17623664, PubMed:18670643, PubMed:20683963, PubMed:20798051, PubMed:21653700, PubMed:7518429, PubMed:8663044).
Interacts with STAT3 (PubMed:26675719)
Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines
Click a pathway to open the interactive Reactome viewer.
Genes with an experimentally identified or computationally predicted synthetic-lethal relationship to FGFR4, aggregated across our SSL data sources. Click any partner node to view that gene’s page.
Nodes and edges are coloured by the SSL data source. Partners appearing in more than one source are shown in grey.
Total Trials Found: 12
| NCT ID | Condition | Brief Title | Phase | Status |
|---|---|---|---|---|
| NCT01752920 | Solid Tumor | Phase 1/2 Study of Derazantinib (ARQ 087) in Adult Subjects With Advanced Solid Tumors With FGFR Genetic Alterations | PHASE1, PHASE2 | COMPLETED |
| NCT02325739 | Hepatocellular Carcinoma (HCC), Solid Malignancies | FGF401 in HCC and Solid Tumors Characterized by Positive FGFR4 and KLB Expression | PHASE1, PHASE2 | COMPLETED |
| NCT02476019 | Obesity | A Safety, Tolerability, PK, and PD Study of Once Weekly ISIS-FGFR4RX SC in Obese Patients | PHASE2 | COMPLETED |
| NCT06258408 | Advanced Solid Tumor | A Phase 1 Study of BB102 in Participants With Advanced Solid Tumors | PHASE1 | RECRUITING |
| NCT04699643 | Advanced Solid Tumors | FGFR4 Inhibitor EVER4010001 in Combination With PD-1 Inhibitor Pembrolizumab in Patients With Advanced Solid Tumors | PHASE1, PHASE2 | UNKNOWN |
| NCT02508467 | Hepatocellular Carcinoma (HCC) | A Phase 1 Study of Fisogatinib (BLU-554) in Patients With Hepatocellular Carcinoma | PHASE1 | COMPLETED |
| NCT07239986 | Hepatocellular Carcinoma (HCC) | A Phase 2 Study of BB102 in Patients With Hepatocellular Carcinoma | PHASE2 | NOT_YET_RECRUITING |
| NCT02272998 | Malignant Neoplasm | Ponatinib for Patients Whose Advanced Solid Tumor Cancer Has Activating Mutations Involving the Following Genes: FGFR1, FGFR2, FGFR3, FGFR4, RET, KIT. | PHASE2 | COMPLETED |
| NCT06865664 | Rhabdomyosarcoma | FGFR4 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory Rhabdomyosarcoma | PHASE1 | RECRUITING |
| NCT06915753 | Metastatic Hepatocellular Carcinoma, Solid Tumors, Solid Tumor, Adult, FGFR Gene Amplification, FGFR Gene Alterations, FGFR3 Gene Alteration, FGFR3 Gene Mutation, Advanced Solid Tumors, FGFR4 Gene Mutation, FGFR4 Gene Fusions, FGF19 Gene Amplification, FGF19 Gene Overexpression, FGFR3 Gene Fusions, Locally Advanced Unresectable Hepatocellular Carcinoma | Safety and Preliminary Anti-Tumor Activity of TYRA-430 in Advanced Hepatocellular Carcinoma and Other Solid Tumors With Activating FGF/FGFR Pathway Aberrations | PHASE1 | RECRUITING |