FGFR1_HUMAN » Fibroblast growth factor receptor 1

FGFR1_HUMAN » Fibroblast growth factor receptor 1
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FGFR1_HUMAN » Fibroblast growth factor receptor 1 » FGFR-1; Basic fibroblast growth factor receptor 1;BFGFR; bFGF-R-1; Fms-like tyrosine kinase 2;FLT-2; N-sam;Proto-oncogene c-Fgr;
Hydrophobic Thickness 27.2 ± 2.2 Å
Tilt Angle 0 ± 3°
ΔGtransfer -30.6 kcal/mol
ΔGfold -12.4 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 372-400 (372-401)
Pathways

Adherens junction (KEGG)

Developmental Biology (Reactome)

Immune System (Reactome)

MAPK signaling pathway (KEGG)

Melanoma (KEGG)

Pathways in cancer (KEGG)

PI3K-Akt signaling pathway (KEGG)

Prostate cancer (KEGG)

Proteoglycans in cancer (KEGG)

Regulation of actin cytoskeleton (KEGG)

Signal Transduction (Reactome)

PDB 2cr3 (38-123), 1agw (456-765), 3tt0 (456-765), 3wj6 (456-765), 1fgi (456-765), 4nks (458-765), 4uwy (458-765), 5am6 (458-765), 3ky2 (458-765), 5am7 (458-765), 4wun (459-765), 3rhx (461-765), 3krj (577-597), 3krl (577-597), 3dpk (577-615), 3kxx (A/B/C/D=458-765), 3gql (A/B/C=458-774), 2fgi (A/B=456-765), 1fgk (A/B=456-765), 4f65 (A/B=458-765), 3js2 (A/B=458-765), 4nka (A/B=458-765), 4f63 (A/B=458-765), 4f64 (A/B=458-765), 4nk9 (A/B=458-765), 3c4f (A/B=464-765), 1xr0 (A=409-430), 3gqi (A=458-774), 1evt (C/D=141-365), 1cvs (C/D=141-365), 1fq9 (C/D=141-365), 3ojv (C/D=142-365)
OPM none
Complexes

FGFR1:FGFR1_HUMAN

Interactions

CADH1, Complex: CADH1:FGFR1, PubMed

EPHA4, Complex: FGFR1:EPHA4, PubMed

ERBB3, Complex: FGFR1:ERBB3, PubMed

FGFR1, Complex: Homodimer of fibroblast growth factor receptor 1, PDBID: 1FGK

FLRT3, Complex: FLRT3:FGFR1, PubMed

I17RD, Complex: I17RD:FGFR1, PubMed

KLOTB, Complex: FGFR1:KLOTB

KLOT, Complex: FGFR1:KLOT:FGF23, PubMed

NCAM1, Complex: FGFR1:NCAM1, PubMed

NRP1, Complex: FGFR1:NRP1, PubMed

Domains

AA: 38-116, PDBID: 2CR3, Subunit A, Seq Identity:100%, Immunoglobulin domain

AA: 160-247, PDBID: 1CVS, Subunit D, Seq Identity:100%, Immunoglobulin I-set domain

AA: 259-358, PDBID: 1CVS, Subunit D, Seq Identity:100%, Immunoglobulin I-set domain

AA: 478-754, PDBID: 1AGW, Subunit B, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for FGFR1_HUMAN » Fibroblast growth factor receptor 1
FUNCTION: Tyrosine-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.

CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

ENZYME REGULATION: Present 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.

SUBUNIT: Monomer. 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).

TISSUE SPECIFICITY: Detected 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.

DOMAIN: The 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.

DISEASE: Pfeiffer syndrome (PS) OMIM: 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). by mutations affecting the gene represented in this entry.

DISEASE: Hypogonadotropic hypogonadism 2 with or without anosmia (HH2) OMIM: 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). 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).

DISEASE: Osteoglophonic dysplasia (OGD) OMIM: Characterized by craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge, as well as by rhizomelic dwarfism and nonossifying bone lesions. Inheritance is autosomal dominant. Note=The disease is caused by mutations affecting the gene represented in this entry.

DISEASE: Hartsfield syndrome (HRTFDS) OMIM: 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. Note=The disease is caused by mutations affecting the gene represented in this entry.

DISEASE: Trigonocephaly 1 (TRIGNO1) OMIM: A keel-shaped deformation of the forehead, caused by premature fusion of the metopic sutures. It results in a triangular shape of the head. mutations affecting the gene represented in this entry.

DISEASE: Note=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.

DISEASE: Note=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.

DISEASE: Note=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.

UniProt features for FGFR1_HUMAN » Fibroblast growth factor receptor 1
SIGNAL 1 21
CHAIN 22 822 Fibroblast growth factor receptor 1.
DOMAIN 25 119 Ig-like C2-type 1.
DOMAIN 158 246 Ig-like C2-type 2.
DOMAIN 255 357 Ig-like C2-type 3.
DOMAIN 478 767 Protein kinase.
REGION 160 177 Heparin-binding.
ACT_SITE 623 623 Proton acceptor.
SITE 428 429 Breakpoint for translocation to form CEP110-FGFR1 OR FGFR1-CEP110 fusion proteins.
SITE 428 429 Breakpoint for translocation to form FGFR1OP-FGFR1 or FGFR1-FGFR1OP fusion proteins.
SITE 428 429 Breakpoint for translocation to form FGFR1OP2-FGFR1.
SITE 766 766 Mediates interaction with PLCG1 and SHB.
DISULFID 55 101 By similarity.
DISULFID 178 230
DISULFID 277 341
Amino Acid Sequence for FGFR1_HUMAN » Fibroblast growth factor receptor 1
MWSWKCLLFW AVLVTATLCT ARPSPTLPEQ AQPWGAPVEV ESFLVHPGDL LQLRCRLRDD VQSINWLRDG VQLAESNRTR ITGEEVEVQD SVPADSGLYA CVTSSPSGSD TTYFSVNVSD ALPSSEDDDD DDDSSSEEKE TDNTKPNRMP VAPYWTSPEK MEKKLHAVPA AKTVKFKCPS SGTPNPTLRW LKNGKEFKPD HRIGGYKVRY ATWSIIMDSV VPSDKGNYTC IVENEYGSIN HTYQLDVVER SPHRPILQAG LPANKTVALG SNVEFMCKVY SDPQPHIQWL KHIEVNGSKI GPDNLPYVQI LKTAGVNTTD KEMEVLHLRN VSFEDAGEYT CLAGNSIGLS HHSAWLTVLE ALEERPAVMT SPLYLEIIIY CTGAFLISCM VGSVIVYKMK SGTKKSDFHS QMAVHKLAKS IPLRRQVTVS ADSSASMNSG VLLVRPSRLS SSGTPMLAGV SEYELPEDPR WELPRDRLVL GKPLGEGCFG QVVLAEAIGL DKDKPNRVTK VAVKMLKSDA TEKDLSDLIS EMEMMKMIGK HKNIINLLGA CTQDGPLYVI VEYASKGNLR EYLQARRPPG LEYCYNPSHN PEEQLSSKDL VSCAYQVARG MEYLASKKCI HRDLAARNVL VTEDNVMKIA DFGLARDIHH IDYYKKTTNG RLPVKWMAPE ALFDRIYTHQ SDVWSFGVLL WEIFTLGGSP YPGVPVEELF KLLKEGHRMD KPSNCTNELY MMMRDCWHAV PSQRPTFKQL VEDLDRIVAL TSNQEYLDLS MPLDQYSPSF PDTRSSTCSS GEDSVFSHEP LPEEPCLPRH PAQLANGGLK RR