ID FGR3_HUMAN STANDARD; PRT; 806 AA. AC P22607; Q14308; Q16294; Q16608; DT 01-AUG-1991 (Rel. 19, Created) DT 01-AUG-1991 (Rel. 19, Last sequence update) DT 15-JUN-2004 (Rel. 44, Last annotation update) DE Fibroblast growth factor receptor 3 precursor (EC 2.7.1.112) (FGFR-3). GN FGFR3 OR JTK4. OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Primates; Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP SEQUENCE FROM N.A. (ISOFORM 1). RX MEDLINE=91142118; PubMed=1847508; RA Keegan K., Johnson D.E., Williams L.T., Hayman M.J.; RT "Isolation of an additional member of the fibroblast growth factor RT receptor family, FGFR-3."; RL Proc. Natl. Acad. Sci. U.S.A. 88:1095-1099(1991). RN [2] RP SEQUENCE FROM N.A. (ISOFORM 3). RA Terada M., Shimizu A., Seo M.; RL Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases. RN [3] RP SEQUENCE OF 76-806 FROM N.A. (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Fetal brain; RX MEDLINE=92147110; PubMed=1664411; RA Thompson L.M., Plummer S., Schalling M., Altherr M.R., Gusella J.F., RA Housman D.E., Wasmuth J.J.; RT "A gene encoding a fibroblast growth factor receptor isolated from the RT Huntington disease gene region of human chromosome 4."; RL Genomics 11:1133-1142(1991). RN [4] RP SEQUENCE OF 614-681 FROM N.A. RX MEDLINE=91062389; PubMed=2247464; RA Partanen J., Maekelae T.P., Alitalo R., Lehvaeslaiho H., RA Alitalo K.; RT "Putative tyrosine kinases expressed in K-562 human leukemia cells."; RL Proc. Natl. Acad. Sci. U.S.A. 87:8913-8917(1990). RN [5] RP SEQUENCE OF 311-358 FROM N.A. (ISOFORM 2). RC TISSUE=Colon tumor; RX MEDLINE=95007529; PubMed=7923141; RA Murgue B., Tsunekawa S., Rosenberg I., deBeaumont M., Podolsky D.K.; RT "Identification of a novel variant form of fibroblast growth factor RT receptor 3 (FGFR3 IIIb) in human colonic epithelium."; RL Cancer Res. 54:5206-5211(1994). RN [6] RP SEQUENCE OF 311-358 FROM N.A. (ISOFORM 2). RC TISSUE=Keratinocytes; RX MEDLINE=96085129; PubMed=7495869; RA Scotet E., Houssaint E.; RT "The choice between alternative IIIb and IIIc exons of the FGFR-3 gene RT is not strictly tissue-specific."; RL Biochim. Biophys. Acta 1264:238-242(1995). RN [7] RP VARIANT ACH ARG-380. RX MEDLINE=94359611; PubMed=8078586; RA Rousseau F., Bonaventure J., Legeai-Mallet L., Pelet A., Rozet J.-M., RA Maroteaux P., le Merrer M., Munnich A.; RT "Mutations in the gene encoding fibroblast growth factor receptor-3 RT in achondroplasia."; RL Nature 371:252-254(1994). RN [8] RP VARIANT ACH ARG-380. RX MEDLINE=95150025; PubMed=7847369; RA Bellus G.A., Hefferon T.W., de Luna R.I., Hecht J.T., Horton W.A., RA Machado M., Kaitila I., McIntosh I., Francomano C.A.; RT "Achondroplasia is defined by recurrent G380R mutations of FGFR3."; RL Am. J. Hum. Genet. 56:368-373(1995). RN [9] RP VARIANT ACH CYS-375. RX MEDLINE=95278277; PubMed=7758520; RA Superti-Furga A., Eich G., Bucher H.U., Wisser J., Giedion A., RA Gitzelmann R., Steinmann B.; RT "A glycine 375-to-cysteine substitution in the transmembrane domain RT of the fibroblast growth factor receptor-3 in a newborn with RT achondroplasia."; RL Eur. J. Pediatr. 154:215-219(1995). RN [10] RP VARIANT TD1 CYS-249. RX MEDLINE=96154693; PubMed=8589699; RA Tavormina P.L., Rimoin D.L., Cohn D.H., Zhu Y.-Z., Shiang R., RA Wasmuth J.J.; RT "Another mutation that results in the substitution of an unpaired RT cysteine residue in the extracellular domain of FGFR3 in RT thanatophoric dysplasia type I."; RL Hum. Mol. Genet. 4:2175-2177(1995). RN [11] RP VARIANTS TD1 CYS-248 AND CYS-371, AND VARIANT TD2 GLU-650. RX MEDLINE=95291326; PubMed=7773297; RA Tavormina P.L., Shiang R., Thompson L.M., Zhu Y.-Z., Wilkin D.J., RA Lachman R.S., Wilcox W.R., Rimoin D.L., Cohn D.H., Wasmuth J.J.; RT "Thanatophoric dysplasia (types I and II) caused by distinct RT mutations in fibroblast growth factor receptor 3."; RL Nat. Genet. 9:321-328(1995). RN [12] RP VARIANT HYPOCHONDROPLASIA LYS-540. RX MEDLINE=95400307; PubMed=7670477; RA Bellus G.A., McIntosh I., Smith E.A., Aylsworth A.S., Kaitila I., RA Horton W.A., Greenhaw G.A., Hecht J.T., Francomano C.A.; RT "A recurrent mutation in the tyrosine kinase domain of fibroblast RT growth factor receptor 3 causes hypochondroplasia."; RL Nat. Genet. 10:357-359(1995). RN [13] RP VARIANT CROUZON GLU-391. RX MEDLINE=96083601; PubMed=7493034; RA Meyers G.A., Orlow S.J., Munro I.R., Przylepa K.A., Jabs E.W.; RT "Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation RT in Crouzon syndrome with acanthosis nigricans."; RL Nat. Genet. 11:462-464(1995). RN [14] RP CHARACTERIZATION OF VARIANT ACH ARG-380. RX MEDLINE=96174812; PubMed=8599935; RA Webster M.K., Donoghue D.J.; RT "Constitutive activation of fibroblast growth factor receptor 3 by RT the transmembrane domain point mutation found in achondroplasia."; RL EMBO J. 15:520-527(1996). RN [15] RP VARIANTS TD1 CYS-248; CYS-249; CYS-370 AND CYS-373. RX MEDLINE=96254981; PubMed=8845844; RA Rousseau F., el Ghouzzi V., Delezoide A.L., Legeai-Mallet L., RA le Merrer M., Munnich A., Bonaventure J.; RT "Missense FGFR3 mutations create cysteine residues in thanatophoric RT dwarfism type I (TD1)."; RL Hum. Mol. Genet. 5:509-512(1996). RN [16] RP VARIANT CRS3 ARG-250. RX MEDLINE=97195541; PubMed=9042914; RA Muenke M., Gripp K.W., McDonald-Mcginn D.M., Gaudenz K., RA Whitaker L.A., Bartlett S.P., Markowitz R.I., Robin N.H., Nwokoro N., RA Mulvihill J.J., Losken H.W., Mulliken J.B., Guttmacher A.E., RA Wilroy R.S., Clarke L.A., Hollway G., Ades L.C., Haan E.A., RA Mulley J.C., Cohen M.M. Jr., Bellus G.A., Francomano C.A., RA Moloney D.M., Wall S.A., Wilkie A.O.M., Zackai E.H.; RT "A unique point mutation in the fibroblast growth factor receptor 3 RT gene (FGFR3) defines a new craniosynostosis syndrome."; RL Am. J. Hum. Genet. 60:555-564(1997). RN [17] RP VARIANT TD1 CYS-370. RX MEDLINE=99004917; PubMed=9790257; RA Katsumata N., Kuno T., Miyazaki S., Mikami S., Nagashima-Miyokawa A., RA Nimura A., Horikawa R., Tanaka T.; RT "G370C mutation in the FGFR3 gene in a Japanese patient with RT thanatophoric dysplasia."; RL Endocr. J. 45:S171-S174(1998). RN [18] RP VARIANT HYPOCHONDROPLASIA VAL-538. RA Grigelioniene G., Hagenaes L., Ekloef O., Neumeyer L., Haereid P.E., RA Anvret M.; RT "A novel missense mutation Ile538Val in the fibroblast growth RT factor receptor 3 in hypochondroplasia."; RL Hum. Mutat. 11:333-333(1998). RN [19] RP VARIANT HYPOCHONDROPLASIA THR-540. RX MEDLINE=98112422; PubMed=9452043; RA Deutz-Terlouw P.P., Losekoot M., Aalfs C.M., Hennekam R.C.M., RA Bakker E.; RT "Asn540Thr substitution in the fibroblast growth factor receptor 3 RT tyrosine kinase domain causing hypochondroplasia."; RL Hum. Mutat. Suppl. 1:S62-S65(1998). RN [20] RP VARIANT TD1 MET-650. RA Kitoh H., Brodie S.G., Kupke K.G., Lachman R.S., Wilcox W.R.; RT "Lys650Met substitution in the tyrosine kinase domain of the RT fibroblast growth factor receptor gene causes thanatophoric dysplasia RT type I."; RL Hum. Mutat. 12:362-363(1998). RN [21] RP VARIANTS BLADDER AND CERVIX CANCERS CYS-248; CYS-249; CYS-370 AND RP GLU-650. RX MEDLINE=99400545; PubMed=10471491; RA Cappellen D., De Oliveira C., Ricol D., Gil Diez de Medina S., RA Bourdin J., Sastre-Garau X., Chopin D., Thiery J.P., Radvanyi F.; RT "Frequent activating mutations of FGFR3 in human bladder and cervix RT carcinomas."; RL Nat. Genet. 23:18-20(1999). RN [22] RP VARIANT HYPOCHONDROPLASIA GLN-650. RX PubMed=11055896; RA Bellus G.A., Spector E.B., Speiser P.W., Weaver C.A., Garber A.T., RA Bryke C.R., Israel J., Rosengren S.S., Webster M.K., Donoghue D.J., RA Francomano C.A.; RT "Distinct missense mutations of the FGFR3 lys650 codon modulate RT receptor kinase activation and the severity of the skeletal dysplasia RT phenotype."; RL Am. J. Hum. Genet. 67:1411-1421(2000). RN [23] RP VARIANT HYPOCHONDROPLASIA SER-540. RX PubMed=10777366; RA Mortier G., Nuytinck L., Craen M., Renard J.-P., Leroy J.G., RA De Paepe A.; RT "Clinical and radiographic features of a family with hypochondroplasia RT owing to a novel asn540ser mutation in the fibroblast growth factor RT receptor 3 gene."; RL J. Med. Genet. 37:220-224(2000). RN [24] RP VARIANT COLORECTAL CANCER LYS-322. RX PubMed=11325814; RA Jang J.-H., Shin K.-H., Park J.-G.; RT "Mutations in fibroblast growth factor receptor 2 and fibroblast RT growth factor receptor 3 genes associated with human gastric and RT colorectal cancers."; RL Cancer Res. 61:3541-3543(2001). RN [25] RP VARIANT BLADDER CANCER GLN-650. RX PubMed=11314002; RA Sibley K., Cuthbert-Heavens D., Knowles M.A.; RT "Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in RT transitional cell carcinoma."; RL Oncogene 20:686-691(2001). RN [26] RP VARIANT HYPOCHONDROPLASIA SER-540. RX PubMed=12707965; RA Thauvin-Robinet C., Faivre L., Lewin P., De Monleon J.-V., RA Francois C., Huet F., Couailler J.-F., Campos-Xavier A.B., RA Bonaventure J., Le Merrer M.; RT "Hlypochondroplasia and stature within normal limits: another family RT with an asn540-to-ser mutation in the fibroblast growth factor RT receptor 3 gene."; RL Am. J. Med. Genet. 119A:81-84(2003). CC -!- FUNCTION: Receptor for acidic and basic fibroblast growth factors. CC Preferentially binds FGF1. CC -!- CATALYTIC ACTIVITY: ATP + a protein tyrosine = ADP + protein CC tyrosine phosphate. CC -!- SUBCELLULAR LOCATION: Type I membrane protein. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; Synonyms=IIIc; CC IsoId=P22607-1; Sequence=Displayed; CC Name=2; Synonyms=IIIb; CC IsoId=P22607-2; Sequence=VSP_002988; CC Name=3; CC IsoId=P22607-3; Sequence=VSP_002989; CC -!- TISSUE SPECIFICITY: Expressed in brain, kidney and testis. Very CC low or no expression in spleen, heart, and muscle. In 20- to 22- CC week old fetuses it is expressed at high level in kidney, lung, CC small intestine and brain, and to a lower degree in spleen, liver, CC and muscle. Epithelial cells show exclusively isoform 2 CC transcripts while fibroblastic cells show a mixture of isoforms 1 CC and 2 transcripts. CC -!- DISEASE: Defects in FGFR3 are the cause of achondroplasia (ACH) CC [MIM:100800]. ACH is an autosomal dominant disease and is the most CC frequent form of short-limb dwarfism. It is characterized by a CC long, narrow trunk, short extremities, particularly in the CC proximal (rhizomelic) segments, a large head with frontal bossing, CC hypoplasia of the midface and a trident configuration of the CC hands. CC -!- DISEASE: Defects in FGFR3 are a cause of Crouzon syndrome CC [MIM:123500]; also called craniofacial dysostosis type I (CFD1). CC Crouzon syndrome is characterized by craniosynostosis (premature CC fusion of the skull sutures), hypertelorism, exophthalmos and CC external strabismus, parrot-beaked nose, short upper lip, CC hypoplastic maxilla, and a relative mandibular prognathism. CC -!- DISEASE: Defects in FGFR3 are a cause of thanatophoric dysplasia CC (TD) [MIM:187600, 187601]; also known as thanatophoric dwarfism. CC TD is the most common neonatal lethal skeletal dysplasia. Affected CC individuals display features similar to those seen in homozygous CC achondroplasia. It causes severe shortening of the limbs with CC macrocephaly, narrow thorax and short ribs. In the most common CC subtype, TD1 [MIM:187600], femur are curved, while in TD2 CC [MIM:187601], straight femurs are associated with cloverleaf CC skull. Mutations affecting different functional domains of FGFR3 CC cause different forms of this lethal disorder. CC -!- DISEASE: Defects in FGFR3 are a cause of craniosynostosis Adelaide CC type (CRSA) [MIM:600593]. CRSA is a form of coronal synostosis CC (CS) characterized by craniosynostosis, midface hypoplasia, CC downslanding palpebral fissures, ptosis, highly arched palate, CC mid-to-moderate sensorineural hearing loss, normal stature, CC bradydactyly and broad big toes. Radiologically, hands and feet CC show thimble-like middle phalanges, coned epiphyses, and carpal CC and tarsal fusions. CC -!- DISEASE: Defects in FGFR3 are a cause of hypochondroplasia (HCH) CC [MIM:146000]. HCH is an autosomal dominant disease and is CC characterized by disproportionate short stature. It resembles CC achondroplasia, but with a less severe phenotype. CC -!- DISEASE: Defects in FGFR3 are a cause of bladder cancer CC [MIM:109800]. Somatic mutations can constitutively activate CC FGFR3. CC -!- DISEASE: Defects in FGFR3 are a cause of cervical cancer CC [MIM:603956]. CC -!- DISEASE: Involved in multiple myeloma (MM) through a chromosomal CC translocation t(4;14)(p16.3;q32.3) which invoves FGFR3 and the IgH CC locus (14q32). CC -!- SIMILARITY: Belongs to the fibroblast growth factor receptor CC family. CC -!- SIMILARITY: Contains 3 immunoglobulin-like C2-type domains. CC -!- DATABASE: NAME=Atlas Genet. Cytogenet. Oncol. Haematol.; CC WWW="http://www.infobiogen.fr/services/chromcancer/Genes/FGFR99.html". CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M58051; AAA52450.1; -. DR EMBL; AF245114; AAF63380.1; -. DR EMBL; M64347; AAA58470.1; -. DR EMBL; M59374; AAA63209.1; -. DR EMBL; S76733; AAB33323.1; -. DR EMBL; X84939; CAA59334.1; -. DR EMBL; U22410; AAA67781.1; -. DR PIR; A38576; TVHUF3. DR HSSP; P11362; 1FGK. DR Genew; HGNC:3690; FGFR3. DR MIM; 134934; -. DR MIM; 100800; -. DR MIM; 123500; -. DR MIM; 146000; -. DR MIM; 187600; -. DR MIM; 187601; -. DR MIM; 600593; -. DR MIM; 109800; -. DR MIM; 603956; -. DR GO; GO:0005887; C:integral to plasma membrane; TAS. DR GO; GO:0005007; F:fibroblast growth factor receptor activity; NAS. DR GO; GO:0016049; P:cell growth; NAS. DR GO; GO:0008543; P:fibroblast growth factor receptor signaling...; TAS. DR GO; GO:0007259; P:JAK-STAT cascade; TAS. DR GO; GO:0000165; P:MAPKKK cascade; TAS. DR GO; GO:0001501; P:skeletal development; TAS. DR InterPro; IPR007110; Ig-like. DR InterPro; IPR003598; Ig_c2. DR InterPro; IPR000719; Prot_kinase. DR InterPro; IPR001245; Tyr_pkinase. DR InterPro; IPR008266; Tyr_pkinase_AS. DR Pfam; PF00047; ig; 3. DR Pfam; PF00069; pkinase; 1. DR PRINTS; PR00109; TYRKINASE. DR ProDom; PD000001; Prot_kinase; 1. DR PROSITE; PS50835; IG_LIKE; 3. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1. KW Receptor; Glycoprotein; Tyrosine-protein kinase; ATP-binding; KW Transferase; Phosphorylation; Transmembrane; Immunoglobulin domain; KW Repeat; Signal; Chromosomal translocation; Disease mutation; KW Alternative splicing; Dwarfism. FT SIGNAL 1 22 FT CHAIN 23 806 Fibroblast growth factor receptor 3. FT DOMAIN 23 375 Extracellular (Potential). FT TRANSMEM 376 396 Potential. FT DOMAIN 397 806 Cytoplasmic (Potential). FT DOMAIN 39 125 Ig-like C2-type 1. FT DOMAIN 151 244 Ig-like C2-type 2. FT DOMAIN 253 355 Ig-like C2-type 3. FT DOMAIN 472 761 Protein kinase. FT NP_BIND 478 486 ATP (By similarity). FT BINDING 508 508 ATP (By similarity). FT ACT_SITE 617 617 By similarity. FT MOD_RES 648 648 Phosphotyrosine (by autocatalysis) (By FT similarity). FT DISULFID 61 109 Potential. FT DISULFID 176 228 Potential. FT DISULFID 275 339 Potential. FT CARBOHYD 98 98 N-linked (GlcNAc...) (Potential). FT CARBOHYD 225 225 N-linked (GlcNAc...) (Potential). FT CARBOHYD 262 262 N-linked (GlcNAc...) (Potential). FT CARBOHYD 294 294 N-linked (GlcNAc...) (Potential). FT CARBOHYD 315 315 N-linked (GlcNAc...) (Potential). FT CARBOHYD 328 328 N-linked (GlcNAc...) (Potential). FT VARSPLIC 311 358 TAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHS FT AWLVVLP -> SWISESVEADVRLRLANVSERDGGEYLCRA FT TNFIGVAEKAFWLSVHGPRA (in isoform 2). FT /FTId=VSP_002988. FT VARSPLIC 311 422 Missing (in isoform 3). FT /FTId=VSP_002989. FT VARIANT 248 248 R -> C (in TD1; severe and lethal and in FT bladder cancer). FT /FTId=VAR_004148. FT VARIANT 249 249 S -> C (in TD1, bladder cancer and FT cervical cancer). FT /FTId=VAR_004149. FT VARIANT 250 250 P -> R (in CRS3). FT /FTId=VAR_004150. FT VARIANT 322 322 E -> K (in colorectal cancer). FT /FTId=VAR_018388. FT VARIANT 370 370 G -> C (in TD1 and bladder cancer). FT /FTId=VAR_004151. FT VARIANT 371 371 S -> C (in TD1). FT /FTId=VAR_004152. FT VARIANT 373 373 Y -> C (in TD1). FT /FTId=VAR_004153. FT VARIANT 375 375 G -> C (in ACH). FT /FTId=VAR_004154. FT VARIANT 380 380 G -> R (in ACH; results in constitutive FT activation; very common mutation, 97% of FT all reported cases). FT /FTId=VAR_004155. FT VARIANT 391 391 A -> E (in Crouzon syndrome with FT acanthosis nigricans). FT /FTId=VAR_004156. FT VARIANT 538 538 I -> V (in hypochondroplasia). FT /FTId=VAR_004157. FT VARIANT 540 540 N -> K (in hypochondroplasia). FT /FTId=VAR_004158. FT VARIANT 540 540 N -> S (in hypochondroplasia; mild). FT /FTId=VAR_018389. FT VARIANT 540 540 N -> T (in hypochondroplasia). FT /FTId=VAR_004159. FT VARIANT 650 650 K -> E (in TD2 and bladder cancer). FT /FTId=VAR_004160. FT VARIANT 650 650 K -> M (in TD1 and ACH). FT /FTId=VAR_004161. FT VARIANT 650 650 K -> Q (in hypochondroplasia and bladder FT cancer; in hypochondroplasia the form is FT milder than that seen in individuals with FT the K-540 or M-650 mutations). FT /FTId=VAR_018390. FT CONFLICT 395 395 L -> V (in Ref. 3). SQ SEQUENCE 806 AA; 87709 MW; BC5EA75EA46F447E CRC64; MGAPACALAL CVAVAIVAGA SSESLGTEQR VVGRAAEVPG PEPGQQEQLV FGSGDAVELS CPPPGGGPMG PTVWVKDGTG LVPSERVLVG PQRLQVLNAS HEDSGAYSCR QRLTQRVLCH FSVRVTDAPS SGDDEDGEDE AEDTGVDTGA PYWTRPERMD KKLLAVPAAN TVRFRCPAAG NPTPSISWLK NGREFRGEHR IGGIKLRHQQ WSLVMESVVP SDRGNYTCVV ENKFGSIRQT YTLDVLERSP HRPILQAGLP ANQTAVLGSD VEFHCKVYSD AQPHIQWLKH VEVNGSKVGP DGTPYVTVLK TAGANTTDKE LEVLSLHNVT FEDAGEYTCL AGNSIGFSHH SAWLVVLPAE EELVEADEAG SVYAGILSYG VGFFLFILVV AAVTLCRLRS PPKKGLGSPT VHKISRFPLK RQVSLESNAS MSSNTPLVRI ARLSSGEGPT LANVSELELP ADPKWELSRA RLTLGKPLGE GCFGQVVMAE AIGIDKDRAA KPVTVAVKML KDDATDKDLS DLVSEMEMMK MIGKHKNIIN LLGACTQGGP LYVLVEYAAK GNLREFLRAR RPPGLDYSFD TCKPPEEQLT FKDLVSCAYQ VARGMEYLAS QKCIHRDLAA RNVLVTEDNV MKIADFGLAR DVHNLDYYKK TTNGRLPVKW MAPEALFDRV YTHQSDVWSF GVLLWEIFTL GGSPYPGIPV EELFKLLKEG HRMDKPANCT HDLYMIMREC WHAAPSQRPT FKQLVEDLDR VLTVTSTDEY LDLSAPFEQY SPGGQDTPSS SSSGDDSVFA HDLLPPAPPS SGGSRT //