UniProt functional annotation for P22455



	UniProt functional annotation for P22455

UniProt code: P22455.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: 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. {ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20018895, ECO:0000269|PubMed:20683963, ECO:0000269|PubMed:20798051, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21653700, ECO:0000269|PubMed:7518429, ECO:0000269|PubMed:7680645, ECO:0000269|PubMed:8663044}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:18670643};

Activity regulation: Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by autophosphorylation on tyrosine residues. {ECO:0000269|PubMed:18480409}.

Subunit: 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). {ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:20683963, ECO:0000269|PubMed:20798051, ECO:0000269|PubMed:21653700, ECO:0000269|PubMed:26675719, ECO:0000269|PubMed:7518429, ECO:0000269|PubMed:8663044}.

Subcellular location: Cell membrane; Single-pass type I membrane protein. Endosome. Endoplasmic reticulum. Note=Internalized from the cell membrane to recycling endosomes, and from there back to the cell membrane.

Subcellular location: [Isoform 2]: Secreted.

Subcellular location: [Isoform 3]: Cytoplasm {ECO:0000269|PubMed:11781352}.

Tissue specificity: Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines. {ECO:0000269|PubMed:10631118}.

Ptm: N-glycosylated. Full maturation of the glycan chains in the Golgi is essential for high affinity interaction with FGF19.

Ptm: Ubiquitinated. Subject to proteasomal degradation when not fully glycosylated. {ECO:0000269|PubMed:18480409}.

Ptm: Autophosphorylated. Binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization and autophosphorylation on tyrosine residues. Autophosphorylation occurs in trans between the two FGFR molecules present in the dimer. {ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:7518429}.

Disease: Prostate cancer (PC) [MIM:176807]: A malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. {ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:18756523, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21349172}. Note=The gene represented in this entry is involved in disease pathogenesis. FGFR4 variant Arg-388 has been associated with prostate cancer as well as cancers of the breast, colon, head and neck, larynx, lung, skin. Arg-388 predisposes cancer patients for accelerated disease progression and is associated with poor prognosis. {ECO:0000269|PubMed:11781352, ECO:0000269|PubMed:11830541, ECO:0000269|PubMed:18670643, ECO:0000269|PubMed:18756523, ECO:0000269|PubMed:20638838, ECO:0000269|PubMed:20876804, ECO:0000269|PubMed:21349172, ECO:0000269|PubMed:21412156, ECO:0000269|PubMed:21882254, ECO:0000269|PubMed:26675719}.

Miscellaneous: [Isoform 3]: Lacks a signal peptide. Constitutively phosphorylated. {ECO:0000305}.

Similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		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. {ECO:0000269\|PubMed:11433297, ECO:0000269\|PubMed:16597617, ECO:0000269\|PubMed:17311277, ECO:0000269\|PubMed:17623664, ECO:0000269\|PubMed:18480409, ECO:0000269\|PubMed:18670643, ECO:0000269\|PubMed:20018895, ECO:0000269\|PubMed:20683963, ECO:0000269\|PubMed:20798051, ECO:0000269\|PubMed:20876804, ECO:0000269\|PubMed:21653700, ECO:0000269\|PubMed:7518429, ECO:0000269\|PubMed:7680645, ECO:0000269\|PubMed:8663044}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10028, ECO:0000269\|PubMed:11433297, ECO:0000269\|PubMed:17311277, ECO:0000269\|PubMed:18480409, ECO:0000269\|PubMed:18670643};
Activity regulation:		Present in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by autophosphorylation on tyrosine residues. {ECO:0000269\|PubMed:18480409}.
Subunit:		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). {ECO:0000269\|PubMed:11433297, ECO:0000269\|PubMed:16597617, ECO:0000269\|PubMed:17623664, ECO:0000269\|PubMed:18670643, ECO:0000269\|PubMed:20683963, ECO:0000269\|PubMed:20798051, ECO:0000269\|PubMed:21653700, ECO:0000269\|PubMed:26675719, ECO:0000269\|PubMed:7518429, ECO:0000269\|PubMed:8663044}.
Subcellular location:		Cell membrane; Single-pass type I membrane protein. Endosome. Endoplasmic reticulum. Note=Internalized from the cell membrane to recycling endosomes, and from there back to the cell membrane.
Subcellular location:		[Isoform 2]: Secreted.
Subcellular location:		[Isoform 3]: Cytoplasm {ECO:0000269\|PubMed:11781352}.
Tissue specificity:		Expressed in gastrointestinal epithelial cells, pancreas, and gastric and pancreatic cancer cell lines. {ECO:0000269\|PubMed:10631118}.
Ptm:		N-glycosylated. Full maturation of the glycan chains in the Golgi is essential for high affinity interaction with FGF19.
Ptm:		Ubiquitinated. Subject to proteasomal degradation when not fully glycosylated. {ECO:0000269\|PubMed:18480409}.
Ptm:		Autophosphorylated. Binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization and autophosphorylation on tyrosine residues. Autophosphorylation occurs in trans between the two FGFR molecules present in the dimer. {ECO:0000269\|PubMed:17311277, ECO:0000269\|PubMed:18670643, ECO:0000269\|PubMed:7518429}.
Disease:		Prostate cancer (PC) [MIM:176807]: A malignancy originating in tissues of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. {ECO:0000269\|PubMed:18670643, ECO:0000269\|PubMed:18756523, ECO:0000269\|PubMed:20876804, ECO:0000269\|PubMed:21349172}. Note=The gene represented in this entry is involved in disease pathogenesis. FGFR4 variant Arg-388 has been associated with prostate cancer as well as cancers of the breast, colon, head and neck, larynx, lung, skin. Arg-388 predisposes cancer patients for accelerated disease progression and is associated with poor prognosis. {ECO:0000269\|PubMed:11781352, ECO:0000269\|PubMed:11830541, ECO:0000269\|PubMed:18670643, ECO:0000269\|PubMed:18756523, ECO:0000269\|PubMed:20638838, ECO:0000269\|PubMed:20876804, ECO:0000269\|PubMed:21349172, ECO:0000269\|PubMed:21412156, ECO:0000269\|PubMed:21882254, ECO:0000269\|PubMed:26675719}.
Miscellaneous:		[Isoform 3]: Lacks a signal peptide. Constitutively phosphorylated. {ECO:0000305}.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily. {ECO:0000255\|PROSITE-ProRule:PRU00159}.