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basic fibroblast growth factor receptor 1; FGFR-1; bFGF-R; Fms-like tyrosine kinase 2; c-fgr; CD331 (FGFR1, FGFBR, FLG, FLT2)

Function: - receptor tyrosine-protein kinase - receptor fibroblast growth factors (FGF) - role in regulation of embryonic development, cell proliferation, differentiation & migration - required for normal mesoderm patterning & correct axial organization during embryonic development, normal development of the skeleton & normal development of the gonadotropin-releasing hormone (GnRH) neuronal system - phosphorylates PLCG1, FRS2, GAB1 & SHB - ligand binding leads to activation of several signaling cascades - activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol & inositol 1,4,5-trisphosphate - phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 & SOS1, & mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 & the MAP kinase signaling pathway, & the AKT1 signaling pathway - promotes phosphorylation of SHC1, STAT1 & PTPN11/SHP2 - in the nucleus, enhances RPS6KA1 & CREB1 activity & contributes to regulation of transcription - FGFR1 signaling is down-regulated by IL17RD/SEF, & by FGFR1 ubiquitination, internalization & degradation - present in an inactive conformation in the absence of bound ligand. - ligand binding leads to dimerization & activation by sequential autophosphorylation on Tyr - autophosphrylated - binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization & autophosphorylation on Tyr - autophosphorylation occurs in trans between the 2 FGFR molecules present in the dimer & proceeds in a highly ordered manner - initial autophosphorylation at Tyr-653 increases the kinase activity by a factor of 50-100 - after this, Tyr-583 becomes phosphorylated, followed by phosphorylation of Tyr-463, Tyr-766, Tyr-583 & Tyr-58 - in a 3rd stage, Tyr-654 is autophosphorylated, resulting in a further tenfold increase of kinase activity - phospho-Tyr provide docking sites for interacting proteins & so are crucial for FGFR1 function & its regulation - ubiquitinated - FGFR1 is rapidly ubiquitinated by NEDD4 after autophosphorylation, leading to internalization & lysosomal degradation - CBL is recruited to activated FGFR1 via FRS2 & GRB2, & mediates ubiquitination & subsequent degradation of FGFR1 - N-glycosylated in the endoplasmic reticulum - the N-glycan chains undergo further maturation to an endo H-resistant form in the Golgi - monomer. homodimer after ligand binding - interacts predominantly with FGF1 & FGF2, but can also interact with FGF3, FGF4, FGF5, FGF6, FGF8, FGF10, FGF19, FGF21, FGF22 & FGF23 (in vitro) - ligand specificity is determined by tissue-specific expression of isoforms, & differences in the 3rd Ig-like domain are crucial for ligand specificity - affinity for fibroblast growth factors (FGFs) is increased by heparan sulfate glycosaminoglycans that function as coreceptors - likewise, KLB increases the affinity for FGF19, FGF21 & FGF23 - interacts (phosphorylated on Tyr-766) with PLCG1 (via SH2 domains) - interacts with FRS2 - interacts (via C-terminus) with NEDD4 (via WW3 domain) - interacts with KL (putative) - interacts with SHB (via SH2 domain) & GRB10 - interacts with KAL1 - this interaction does not interfere with FGF2-binding to FGFR1, but prevents binding of heparin-bound FGF2 - interacts with SOX2 & SOX3 Inhibition: - inhibited by ARQ 069; this compound maintains the kinase in an inactive conformation & inhibits autophosphorylation - inhibited by PD173074 Structure: - the 2nd & 3rd Ig-like domains directly interact with FGF & heparan sulfate proteoglycans - isoforms lacking the first Ig-like domain have higher affinity for FGF & heparan sulfate proteoglycans than isoforms with all 3 Ig-like domains - belongs to the protein kinase superfamily, Tyr protein kinase family, fibroblast growth factor receptor subfamily - contains 3 Ig-like C2-type domain (immunoglobulin-like) domains - contains 1 protein kinase domain Compartment: - membrane, single-pass type 1 membrane protein - nucleus, cytoplasm, cytoplasmic vesicle - after ligand binding, both receptor & ligand are rapidly internalized - can translocate to the nucleus after internalization, or by translocation from the endoplasmic reticulum or Golgi to the cytosol, & from there to the nucleus Alternative splicing: named isoforms=21 Expression: - found mainly in CNS - some isoforms are detected in foreskin fibroblast cell lines Pathology: - detected in astrocytoma, neuroblastoma & adrenal cortex cell lines - defects in FGFR1 are a cause of: a) Pfeiffer syndrome b) isolated hypogonadotropic hypogonadism c) Kallmann syndrome type 2 d) osteoglophonic dysplasia e) non-syndromic trigonocephaly - chromosomal translocation t(8;13)(p11;q12) involving FGFR1 with with ZMYM2 may be a cause of stem cell leukemia lymphoma syndrome (SCLL) - chromosomal translocations involving FGFR1 t(6;8)(q27;p11) with FGFR1OP & t(8;9)(p12;q33) with CEP110 & insertion ins(12;8)(p11;p11p22) with FGFR1OP2 may be causes of stem cell myeloproliferative disorder (MPD) - fusion proteins FGFR1OP2-FGFR1, FGFR1OP-FGFR1 or FGFR1-FGFR1OP may exhibit constitutive kinase activity & be responsible for the transforming activity

Related

FGFR1 gene mutation FGFR1 or FLT2 gene

General

cluster-of-differentiation antigen; cluster designation antigen; CD antigen fibroblast growth factor [FGF] receptor human longevity protein

Properties

SIZE: entity length = 822 aa MW = 92 kD COMPARTMENT: cellular membrane STATE: active state MOTIF: signal sequence {1-21} immunoglobulin superfamily domain {25-119} MOTIF: cysteine residue {C55} MODIFICATION: cysteine residue {C101} N-glycosylation site {N77} cysteine residue {C101} MODIFICATION: cysteine residue {C55} N-glycosylation site {N117} immunoglobulin superfamily domain {158-246} MOTIF: binding site SITE: 160-177 FOR-BINDING-OF: heparin cysteine residue {C178} MODIFICATION: cysteine residue {C230} N-glycosylation site {N227} cysteine residue {C230} MODIFICATION: cysteine residue {C178} N-glycosylation site {N240} immunoglobulin superfamily domain {255-357} MOTIF: N-glycosylation site {N264} cysteine residue {C277} MODIFICATION: cysteine residue {C341} N-glycosylation site {N296} N-glycosylation site {N317} N-glycosylation site {N330} cysteine residue {C341} MODIFICATION: cysteine residue {C277} transmembrane domain {377-397} breakpoint {428-429} kinase domain SITE: 478-767 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 484-492 ATP-binding site NAME: ATP-binding site SITE: 514-514 aspartate residue {D623} Tyr phosphorylation site {Y653} Tyr phosphorylation site {Y654} tyrosine residue {766} Tyr phosphorylation site {Y766}

Database Correlations

OMIM correlations MORBIDMAP 136350 UniProt P11362 PFAM correlations Entrez Gene 2260 Kegg hsa:2260 ENZYME correlations

References

  1. UniProt :accession P11362
  2. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/FGFR1113.html
  3. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=FGFR1
  4. Cross M, Dexter TM. Growth factors in development, transformation, and tumorigenesis. Cell. 1991 Jan 25;64(2):271-80. Review. PMID: 1988148
  5. Partanen J et al FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. EMBO J. 1991 Jun;10(6):1347-54. PMID: 1709094
  6. NIEHS-SNPs http://egp.gs.washington.edu/data/fgfr1/