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MGP001073

UniProt Annotations

Entry Information
Gene Namefibroblast growth factor receptor 1
Protein EntryFGFR1_HUMAN
UniProt IDP11362
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=21; Name=1; Synonyms=Alpha A1, IV; IsoId=P11362-1; Sequence=Displayed; Name=2; Synonyms=Alpha A2; IsoId=P11362-8; Sequence=VSP_009842, VSP_009843; Name=3; Synonyms=Alpha A3; IsoId=P11362-17; Sequence=VSP_009836, VSP_009837; Name=4; Synonyms=Alpha B1; IsoId=P11362-2; Sequence=VSP_002960; Name=5; Synonyms=Alpha B2; IsoId=P11362-9; Sequence=VSP_002960, VSP_009842, VSP_009843; Name=6; Synonyms=Beta A1, II, H2; IsoId=P11362-3; Sequence=VSP_002958; Name=7; Synonyms=Beta A2; IsoId=P11362-10; Sequence=VSP_002958, VSP_009842, VSP_009843; Name=8; Synonyms=Beta B1; IsoId=P11362-4; Sequence=VSP_002958, VSP_002960; Name=9; Synonyms=Beta B2; IsoId=P11362-11; Sequence=VSP_002958, VSP_002960, VSP_009842, VSP_009843; Name=10; Synonyms=Gamma A1; IsoId=P11362-5; Sequence=VSP_002957; Name=11; Synonyms=Gamma A2; IsoId=P11362-12; Sequence=VSP_002957, VSP_009842, VSP_009843; Name=12; Synonyms=Gamma B1; IsoId=P11362-6; Sequence=VSP_002957, VSP_002960; Name=13; Synonyms=Gamma B2; IsoId=P11362-13; Sequence=VSP_002957, VSP_002960, VSP_009842, VSP_009843; Name=14; Synonyms=A, III; IsoId=P11362-7; Sequence=VSP_002959; Name=15; Synonyms=I, H3; IsoId=P11362-14; Sequence=VSP_002958, VSP_002959; Name=16; Synonyms=V; IsoId=P11362-15; Sequence=VSP_009838, VSP_009839; Name=17; Synonyms=H4; IsoId=P11362-16; Sequence=VSP_002958, VSP_009840, VSP_009841; Name=18; Synonyms=H5; IsoId=P11362-18; Sequence=VSP_002958, VSP_002959, VSP_009840, VSP_009841; Name=19; IsoId=P11362-19; Sequence=VSP_038470, VSP_002959, VSP_038471; Name=20; IsoId=P11362-20; Sequence=VSP_041916, VSP_041918; Name=21; IsoId=P11362-21; Sequence=VSP_041917, VSP_002959;
Catalytic ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE- ProRule:PRU10028, ECO:0000269|PubMed:1379697, ECO:0000269|PubMed:15117958, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:19224897, ECO:0000269|PubMed:19665973, ECO:0000269|PubMed:20133753, ECO:0000269|PubMed:8622701}.
DiseaseHartsfield syndrome (HRTFDS) [MIM:615465]: A syndrome characterized by the triad of holoprosencephaly, ectrodactyly, and cleft/lip palate. Profound mental retardation is also present. Multiple other congenital anomalies usually occur. {ECO:0000269|PubMed:23812909, ECO:0000269|PubMed:24888332}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseHypogonadotropic hypogonadism 2 with or without anosmia (HH2) [MIM:147950]: A disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. In some cases, it is associated with non- reproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss. Anosmia or hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to deficiency in gonadotropin-releasing hormone and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism is referred to as Kallmann syndrome, whereas in the presence of a normal sense of smell, it has been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). {ECO:0000269|PubMed:12627230, ECO:0000269|PubMed:15001591, ECO:0000269|PubMed:15605412, ECO:0000269|PubMed:15845591, ECO:0000269|PubMed:16606836, ECO:0000269|PubMed:16757108, ECO:0000269|PubMed:16764984, ECO:0000269|PubMed:16882753, ECO:0000269|PubMed:17154279, ECO:0000269|PubMed:19820032, ECO:0000269|PubMed:21700882, ECO:0000269|PubMed:22927827, ECO:0000269|PubMed:23643382}. Note=The disease is caused by mutations affecting distinct genetic loci, including the gene represented in this entry. Some patients carrying mutations in FGFR1 also have a mutation other HH-associated genes including DUSP6, FGF8, FGF17, FLRT3, GNRH1, GNRHR, HS6ST1, IL17RD, KAL1, KISS1R, NSMF, PROKR2, SPRY4 and TACR3 (PubMed:23643382). {ECO:0000269|PubMed:23643382}.
DiseaseNote=A chromosomal aberration involving FGFR1 may be a cause of stem cell leukemia lymphoma syndrome (SCLL). Translocation t(8;13)(p11;q12) with ZMYM2. SCLL usually presents as lymphoblastic lymphoma in association with a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow.
DiseaseNote=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(6;8)(q27;p11) with FGFR1OP. Insertion ins(12;8)(p11;p11p22) with FGFR1OP2. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion proteins FGFR1OP2-FGFR1, FGFR1OP-FGFR1 or FGFR1-FGFR1OP may exhibit constitutive kinase activity and be responsible for the transforming activity.
DiseaseNote=A chromosomal aberration involving FGFR1 may be a cause of stem cell myeloproliferative disorder (MPD). Translocation t(8;9)(p12;q33) with CNTRL. MPD is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia. The fusion protein CNTRL-FGFR1 is found in the cytoplasm, exhibits constitutive kinase activity and may be responsible for the transforming activity.
DiseaseOsteoglophonic dysplasia (OGD) [MIM:166250]: Characterized by craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as by rhizomelic dwarfism and nonossifying bone lesions. Inheritance is autosomal dominant. {ECO:0000269|PubMed:15625620, ECO:0000269|PubMed:16470795}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseasePfeiffer syndrome (PS) [MIM:101600]: A syndrome characterized by the association of craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly of the fingers and toes. Three subtypes are known: mild autosomal dominant form (type 1); cloverleaf skull, elbow ankylosis, early death, sporadic (type 2); craniosynostosis, early demise, sporadic (type 3). {ECO:0000269|PubMed:7874169}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseTrigonocephaly 1 (TRIGNO1) [MIM:190440]: A keel-shaped deformation of the forehead, caused by premature fusion of the metopic sutures. It results in a triangular shape of the head. {ECO:0000269|PubMed:11173846}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DomainThe second and third Ig-like domains directly interact with fibroblast growth factors (FGF) and heparan sulfate proteoglycans. Isoforms lacking the first Ig-like domain have higher affinity for fibroblast growth factors (FGF) and heparan sulfate proteoglycans than isoforms with all three Ig-like domains.
Enzyme RegulationPresent in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by sequential autophosphorylation on tyrosine residues. Inhibited by ARQ 069; this compound maintains the kinase in an inactive conformation and inhibits autophosphorylation. Inhibited by PD173074. {ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:19224897, ECO:0000269|PubMed:21454610, ECO:0000269|PubMed:8622701}.
FunctionTyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration. Required for normal mesoderm patterning and correct axial organization during embryonic development, normal skeletogenesis and normal development of the gonadotropin-releasing hormone (GnRH) neuronal system. Phosphorylates PLCG1, FRS2, GAB1 and SHB. 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 phosphorylation of SHC1, STAT1 and PTPN11/SHP2. In the nucleus, enhances RPS6KA1 and CREB1 activity and contributes to the regulation of transcription. FGFR1 signaling is down-regulated by IL17RD/SEF, and by FGFR1 ubiquitination, internalization and degradation. {ECO:0000269|PubMed:10830168, ECO:0000269|PubMed:11353842, ECO:0000269|PubMed:12181353, ECO:0000269|PubMed:1379697, ECO:0000269|PubMed:1379698, ECO:0000269|PubMed:15117958, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:19224897, ECO:0000269|PubMed:19261810, ECO:0000269|PubMed:19665973, ECO:0000269|PubMed:20133753, ECO:0000269|PubMed:20139426, ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:8622701, ECO:0000269|PubMed:8663044}.
InteractionSelf; NbExp=3; IntAct=EBI-1028277, EBI-1028277; P12830:CDH1; NbExp=3; IntAct=EBI-1028277, EBI-727477; P46108:CRK; NbExp=2; IntAct=EBI-1028277, EBI-886; P35222:CTNNB1; NbExp=2; IntAct=EBI-1028277, EBI-491549; P05230:FGF1; NbExp=3; IntAct=EBI-1028277, EBI-698068; P09038:FGF2; NbExp=4; IntAct=EBI-1028277, EBI-977447; O88900:Grb14 (xeno); NbExp=3; IntAct=EBI-1028277, EBI-7639197; P08908:HTR1A; NbExp=11; IntAct=EBI-1028277, EBI-6570214; P23352:KAL1; NbExp=7; IntAct=EBI-1028277, EBI-5272188; P46934:NEDD4; NbExp=26; IntAct=EBI-1028277, EBI-726944; Q8IVI9:NOSTRIN; NbExp=5; IntAct=EBI-1028277, EBI-1391643; P27986:PIK3R1; NbExp=5; IntAct=EBI-1028277, EBI-79464; P19174:PLCG1; NbExp=5; IntAct=EBI-1028277, EBI-79387; P10686:Plcg1 (xeno); NbExp=4; IntAct=EBI-1028277, EBI-520788;
PtmAutophosphorylated. 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 and proceeds in a highly ordered manner. Initial autophosphorylation at Tyr-653 increases the kinase activity by a factor of 50 to 100. After this, Tyr-583 becomes phosphorylated, followed by phosphorylation of Tyr-463, Tyr-766, Tyr-583 and Tyr-585. In a third stage, Tyr-654 is autophosphorylated, resulting in a further tenfold increase of kinase activity. Phosphotyrosine residues provide docking sites for interacting proteins and so are crucial for FGFR1 function and its regulation. {ECO:0000269|PubMed:16507368, ECO:0000269|PubMed:19224897, ECO:0000269|PubMed:19665973, ECO:0000269|PubMed:8622701}.
PtmN-glycosylated in the endoplasmic reticulum. The N-glycan chains undergo further maturation to an Endo H-resistant form in the Golgi apparatus. {ECO:0000269|PubMed:16335952, ECO:0000269|PubMed:16481405, ECO:0000269|PubMed:17311277}.
PtmUbiquitinated. FGFR1 is rapidly ubiquitinated by NEDD4 after autophosphorylation, leading to internalization and lysosomal degradation. CBL is recruited to activated FGFR1 via FRS2 and GRB2, and mediates ubiquitination and subsequent degradation of FGFR1. {ECO:0000269|PubMed:18480409, ECO:0000269|PubMed:21765395}.
Sequence CautionSequence=BAD92156.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305};
SimilarityBelongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 3 Ig-like C2-type (immunoglobulin-like) domains. {ECO:0000305}.
Subcellular LocationCell membrane; Single-pass type I membrane protein. Nucleus. Cytoplasm, cytosol. Cytoplasmic vesicle. Note=After ligand binding, both receptor and ligand are rapidly internalized. Can translocate to the nucleus after internalization, or by translocation from the endoplasmic reticulum or Golgi apparatus to the cytosol, and from there to the nucleus.
SubunitMonomer. Homodimer after ligand binding. Interacts predominantly with FGF1 and FGF2, but can also interact with FGF3, FGF4, FGF5, FGF6, FGF8, FGF10, FGF19, FGF21, FGF22 and FGF23 (in vitro). Ligand specificity is determined by tissue-specific expression of isoforms, and differences in the third 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 and 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 (By similarity). Interacts with SHB (via SH2 domain) and GRB10. Interacts with KAL1; this interaction does not interfere with FGF2-binding to FGFR1, but prevents binding of heparin-bound FGF2. Interacts with SOX2 and SOX3 (By similarity). {ECO:0000250}.
Tissue SpecificityDetected in astrocytoma, neuroblastoma and adrenal cortex cell lines. Some isoforms are detected in foreskin fibroblast cell lines, however isoform 17, isoform 18 and isoform 19 are not detected in these cells. {ECO:0000269|PubMed:1652059}.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/FGFR1ID113.html";
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/fgfr1/";
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