FGFR4

Synonyms

EC 2.7.10, Fibroblast growth factor receptor 4, CD334, FGFR4, TKF, JTK2, Tyrosine Kinase Related To Fibroblast Growth Factor Receptor, Hydroxyaryl-Protein Kinase, Protein-Tyrosine Kinase, Tyrosylprotein Kinase, CD334 Antigen, EC 2.7.10.1, FGFR-4, EC:2.7.10.1, Receptor, Fibroblast Growth Factor, Type 4

Description

Fibroblast growth factor receptor 4 is a protein that in humans is encoded by the FGFR4 gene. FGFR4 has also been designated as CD334 (cluster of differentiation 334).Tyrosine-protein kinase that acts as 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.

KO Status

RenMab: In Vitro

Drug Information

Launched drugs: 2
Drugs in clinical trials: 12
Latest Research Phase: Approved

Drug Name

Code

Phase

Company

Indications

Clinical Trials

Lenvatinib Mesylate

ER-203492-00, E-7080

Approved

Eisai Co Ltd

Liver Neoplasms, Solid tumours, Biliary Tract Neoplasms, Esophageal Neoplasms, Squamous Cell Carcinoma of Head and Neck, Carcinoma, Renal Cell, Renal Insufficiency, Triple Negative Breast Neoplasms, Small Cell Lung Carcinoma, Adenocarcinoma of Lung, Thyroid Carcinoma, Anaplastic, Kidney Diseases, Urinary Bladder Neoplasms, Liver Diseases, Cholangiocarcinoma, Sarcoma, Hepatic Insufficiency, Gallbladder Neoplasms, Endometrial Neoplasms, Thyroid Neoplasms, Lymphoma, Uterine Cervical Neoplasms, Carcinoma, Hepatocellular, Carcinoma, Non-Small-Cell Lung, Melanoma

Erdafitinib

G-024, JNJ-493, 890E37NHMV, JNJ-42756493

Approved

Astex Pharmaceuticals Inc

Solid tumours, Carcinoma, Esophageal Neoplasms, Stomach Neoplasms, Carcinoma, Transitional Cell, Urinary Bladder Neoplasms, Bile Duct Neoplasms, Urologic Neoplasms, Hepatic Insufficiency, Lymphoma, Carcinoma, Hepatocellular, Adenocarcinoma, Carcinoma, Non-Small-Cell Lung

Futibatinib

TAS-120

Phase 3 Clinical

Otsuka Pharmaceutical Co Ltd, Taiho Pharmaceutical Co Ltd

Solid tumours, Bone Marrow Neoplasms, Stomach Neoplasms, Carcinoma, Esophageal Neoplasms, Carcinoma, Transitional Cell, Central Nervous System Neoplasms, Cholangiocarcinoma, Breast Neoplasms, Lymphoma, Carcinoma, Non-Small-Cell Lung

Aldafermin

M-70, NGM-282

Phase 2 Clinical

Ngm Biopharmaceuticals

Constipation, Liver Cirrhosis, Biliary, Non-alcoholic Fatty Liver Disease, Renal Insufficiency, Diabetes Mellitus, Type 2, Fibrosis, Cholangitis, Sclerosing, Hepatic Insufficiency, Diabetes Mellitus

LY-2874455

LY-2874455

Phase 2 Clinical

Eli Lilly And Company

Neoplasms

Roblitinib

FGF-401, NVP-FGF401

Phase 2 Clinical

Novartis Pharma Ag

Solid tumours, Neoplasms, Carcinoma, Hepatocellular

Fisogatinib

BLU-554, CS-3008

Phase 2 Clinical

Blueprint Medicines Corp

Carcinoma, Hepatocellular

SY-4798

Phase 1 Clinical

Shouyao Holding (Beijing) Co Ltd

Solid tumours

PRN-1371

PRN-1371

Phase 1 Clinical

Principia Biopharma Inc

Solid tumours, Urinary Bladder Neoplasms

H3B-6527

H3B-6527

Phase 1 Clinical

H3 Biomedicine

Liver Neoplasms, Cholangiocarcinoma, Carcinoma, Hepatocellular

References


Title

Authors

Source

Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21

Kurosu H., Choi M., Ogawa Y., Dickson A.S., Goetz R., Eliseenkova A.V., Mohammadi M., Rosenblatt K.P., Kliewer S.A., Kuro-o M.,

J. Biol. Chem. 282:26687-26695(2007)

Fibroblast growth factor receptor-induced phosphorylation of STAT1 at the Golgi apparatus without translocation to the nucleus

Citores L., Bai L., Sorensen V., Olsnes S.,

J. Cell. Physiol. 212:148-156(2007)

Polymorphisms of fibroblast growth factor receptor 4 have association with the development of prostate cancer and benign prostatic hyperplasia and the progression of prostate cancer in a Japanese population

Ma Z., Tsuchiya N., Yuasa T., Inoue T., Kumazawa T., Narita S., Horikawa Y., Tsuruta H., Obara T., Saito M., Satoh S., Ogawa O., Habuchi T.,

Int. J. Cancer 123:2574-2579(2008)

Ubiquitination of fibroblast growth factor receptor 1 is required for its intracellular sorting but not for its endocytosis

Haugsten E.M., Malecki J., Bjorklund S.M., Olsnes S., Wesche J.,

Mol. Biol. Cell 19:3390-3403(2008)

Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression

Wang J., Yu W., Cai Y., Ren C., Ittmann M.M.,

Neoplasia 10:847-856(2008)

FGFR4 transmembrane domain polymorphism and cancer risk: a meta-analysis including 8555 subjects

Xu W., Li Y., Wang X., Chen B., Wang Y., Liu S., Xu J., Zhao W., Wu J.,

Eur. J. Cancer 46:3332-3338(2010)

Glycosylation of fibroblast growth factor receptor 4 is a key regulator of fibroblast growth factor 19-mediated down-regulation of cytochrome P450 7A1

Triantis V., Saeland E., Bijl N., Oude-Elferink R.P., Jansen P.L.,

Hepatology 52:656-666(2010)

FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation

Wu X., Ge H., Lemon B., Vonderfecht S., Weiszmann J., Hecht R., Gupte J., Hager T., Wang Z., Lindberg R., Li Y.,

J. Biol. Chem. 285:5165-5170(2010)

FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex

Sugiyama N., Varjosalo M., Meller P., Lohi J., Chan K.M., Zhou Z., Alitalo K., Taipale J., Keski-Oja J., Lehti K.,

Proc. Natl. Acad. Sci. U.S.A. 107:15786-15791(2010)

FGFR4 Gly388Arg polymorphism contributes to prostate cancer development and progression: a meta-analysis of 2618 cases and 2305 controls

Xu B., Tong N., Chen S.Q., Hua L.X., Wang Z.J., Zhang Z.D., Chen M.,

BMC Cancer 11:84-84(2011)