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:
  • Pfeiffer syndrome
  • isolated hypogonadotropic hypogonadism
  • Kallmann syndrome type 2
  • osteoglophonic dysplasia
  • 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

More general terms

• fibroblast growth factor [FGF] receptor
• CD antigen
• human longevity protein

Database

• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:2260
• OMIM: https://mirror.omim.org/entry/101600
• OMIM: https://mirror.omim.org/entry/136350
• OMIM: https://mirror.omim.org/entry/146110
• OMIM: https://mirror.omim.org/entry/147950
• OMIM: https://mirror.omim.org/entry/166250
• OMIM: https://mirror.omim.org/entry/190440
• UniProt: http://www.uniprot.org/uniprot/P11362.html
• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=2260