Reviewed, UniProtKB/Swiss-Prot P22607 (FGFR3_HUMAN)

Names and origin

Protein names

Recommended name:
    Fibroblast growth factor receptor 3
      Short name=FGFR-3
    EC=2.7.10.1
Alternative name(s):
    CD_antigen=CD333

Gene names

Name:	FGFR3
Synonyms:	JTK4

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	806 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Receptor for acidic and basic fibroblast growth factors. Preferentially binds FGF1.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subcellular location	Membrane; Single-pass type I membrane protein.
Tissue specificity	Expressed in brain, kidney and testis. Very low or no expression in spleen, heart, and muscle. In 20- to 22-week old fetuses it is expressed at high level in kidney, lung, small intestine and brain, and to a lower degree in spleen, liver, and muscle. Epithelial cells show exclusively isoform 2 transcripts while fibroblastic cells show a mixture of isoform 1 and isoform 2.
Involvement in disease	Defects in FGFR3 are the cause of achondroplasia (ACH) [MIM:100800]. ACH is an autosomal dominant disease and is the most frequent form of short-limb dwarfism. It is characterized by a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. Defects in FGFR3 are a cause of Crouzon syndrome (CS) [MIM:123500]; also called craniofacial dysostosis type I (CFD1). Crouzon syndrome is characterized by craniosynostosis (premature fusion of the skull sutures), hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism. Defects in FGFR3 are the cause of platyspondylic lethal skeletal dysplasia Sand Diego type (PLSD-SD) [MIM:270230]. Platyspondylic lethal skeletal dysplasias (PLSDs) are a heterogeneous group of chondrodysplasias characterized by severe platyspondyly and limb shortening. PLSD-SD is characterized by postnatal growth deficiency, mild developmental delay, short trunk, craniofacial abnormalities, platyspondyly, delayed ossification, generalized osteoporosis and thin ribs. Defects in FGFR3 are a cause of thanatophoric dysplasia (TD) [MIM:187600, 187601]; also known as thanatophoric dwarfism. TD is the most common neonatal lethal skeletal dysplasia. Affected individuals display features similar to those seen in homozygous achondroplasia. It causes severe shortening of the limbs with macrocephaly, narrow thorax and short ribs. In the most common subtype, TD1, femur are curved, while in TD2, straight femurs are associated with cloverleaf skull. Mutations affecting different functional domains of FGFR3 cause different forms of this lethal disorder. Defects in FGFR3 are a cause of hypochondroplasia (HCH) [MIM:146000]. HCH is an autosomal dominant disease and is characterized by disproportionate short stature. It resembles achondroplasia, but with a less severe phenotype. Defects in FGFR3 are a cause of bladder cancer [MIM:109800]. Somatic mutations can constitutively activate FGFR3. Defects in FGFR3 are a cause of cervical cancer [MIM:603956]. Defects in FGFR3 are the cause of camptodactyly tall stature and hearing loss syndrome (CATSHL syndrome) [MIM:610474]. CATSHL syndrome is an autosomal dominant syndrome characterized by permanent and irreducible flexion of one or more fingers of the hand and/or feet, tall stature, scoliosis and/or a pectus excavatum, and hearing loss. Affected individuals have developmental delay and/or mental retardation, and several of these have microcephaly. Radiographic findings included tall vertebral bodies with irregular borders and broad femoral metaphyses with long tubular shafts. On audiological exam, each tested member have bilateral sensorineural hearing loss and absent otoacoustic emissions. The hearing loss was congenital or developed in early infancy, progressed variably in early childhood, and range from mild to severe. Computed tomography and magnetic resonance imaging reveal that the brain, middle ear, and inner ear are structurally normal. A chromosomal aberration involving FGFR3 may be a cause of multiple myeloma (MM) [MIM:254500]. Translocation t(4;14)(p16.3;q32.3) with the IgH locus. Defects in FGFR3 are a cause of lacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730]; also known as Levy-Hollister syndrome. LADDS is a form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. LADDS is an autosomal dominant syndrome characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies. In addition to these cardinal features, facial dysmorphism, malformations of the kidney and respiratory system and abnormal genitalia have been reported. Craniosynostosis and severe syndactyly are not observed. Defects in FGFR3 are a cause of keratinocytic non-epidermolytic nevus [MIM:162900]; also called pigmented moles. Epidermal nevi of the common, non-organoid and non-epidermolytic type are benign skin lesions and may vary in their extent from a single (usually linear) lesion to widespread and systematized involvement. They may be present at birth or develop early during childhood. Defects in FGFR3 are a cause of Muenke syndrome (MNKS) [MIM:602849]; also known as Muenke non-syndromic coronal craniosynostosis. MNKS is a condition characterized by premature closure of coronal suture of skull during development (coronal craniosynostosis), which affects the shape of the head and face. It may be uni- or bilateral. When bilateral, it is characterized by a skull with a small antero-posterior diameter (brachycephaly), often with a decrease in the depth of the orbits and hypoplasia of the maxillae. Unilateral closure of the coronal sutures leads to flattening of the orbit on the involved side (plagiocephaly). The intellect is normal. In addition to coronal craniosynostosis some affected individuals show skeletal abnormalities of hands and feet, sensorineural hearing loss, mental retardation and respiratory insufficiency.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily. Contains 3 Ig-like C2-type (immunoglobulin-like) domains. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Alternative splicing Chromosomal rearrangement Polymorphism
Disease	Craniosynostosis Deafness Disease mutation Dwarfism Ectodermal dysplasia Lacrimo-auriculo-dento-digital syndrome
Domain	Immunoglobulin domain Repeat Signal Transmembrane
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	JAK-STAT cascade Traceable author statement. Source: ProtInc MAPKKK cascade Traceable author statement. Source: ProtInc cell growth Non-traceable author statement. Source: UniProtKB fibroblast growth factor receptor signaling pathway Traceable author statement. Source: ProtInc protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro sensory perception of sound Inferred from electronic annotation. Source: UniProtKB-KW skeletal system development Traceable author statement. Source: ProtInc
Cellular component	integral to plasma membrane Traceable author statement. Source: ProtInc
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro fibroblast growth factor receptor activity Ref.6 Non-traceable author statement. Source: UniProtKB identical protein binding Ref.8 Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		1	EBI-348399,EBI-348399
FGF1	P05230	2	EBI-348399,EBI-698068
GPSM3	Q9Y4H4	1	EBI-348399,EBI-347538

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P22607-1)

Also known as: IIIc;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P22607-2)

Also known as: IIIb;

The sequence of this isoform differs from the canonical sequence as follows:
     311-358: TAGANTTDKE...HHSAWLVVLP → SWISESVEAD...FWLSVHGPRA

Isoform 3 (identifier: P22607-3)

The sequence of this isoform differs from the canonical sequence as follows:
     311-422: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 22

22

Chain

23 – 806

784

Fibroblast growth factor receptor 3

PRO_0000016785

Regions

Topological domain

23 – 375

353

Extracellular Potential

Transmembrane

376 – 396

21

Potential

Topological domain

397 – 806

410

Cytoplasmic Potential

Domain

24 – 126

103

Ig-like C2-type 1

Domain

151 – 244

94

Ig-like C2-type 2

Domain

253 – 355

103

Ig-like C2-type 3

Domain

472 – 761

290

Protein kinase

Nucleotide binding

478 – 486

9

ATP By similarity

Sites

Active site

617

1

Proton acceptor By similarity

Binding site

508

1

ATP By similarity

Amino acid modifications

Modified residue

647

1

Phosphotyrosine By similarity

Modified residue

648

1

Phosphotyrosine; by autocatalysis By similarity

Glycosylation

98

1

N-linked (GlcNAc...) Potential

Glycosylation

225

1

N-linked (GlcNAc...) Potential

Glycosylation

262

1

N-linked (GlcNAc...) Potential

Glycosylation

294

1

N-linked (GlcNAc...) Potential

Glycosylation

315

1

N-linked (GlcNAc...) Potential

Glycosylation

328

1

N-linked (GlcNAc...) Potential

Disulfide bond

61 ↔ 109

Potential

Disulfide bond

176 ↔ 228

Potential

Disulfide bond

275 ↔ 339

Potential

Natural variations

Alternative sequence

311 – 422

112

Missing in isoform 3.

VSP_002989

Alternative sequence

311 – 358

48

TAGAN…LVVLP → SWISESVEADVRLRLANVSE RDGGEYLCRATNFIGVAEKA FWLSVHGPRA in isoform 2.

VSP_002988

Natural variant

65

1

G → R: dbSNP rs2305178.

VAR_022167

Natural variant

79

1

T → S in a lung adenocarcinoma sample; somatic mutation.

VAR_042207

Natural variant

228

1

C → R in a colorectal adenocarcinoma sample; somatic mutation.

VAR_042208

Natural variant

248

1

R → C in bladder cancer, PLSD-SD, keratinocytic non-epidermolytic nevus and TD; severe and lethal; also found as somatic mutation in one patient with multiple myeloma.

VAR_004148

Natural variant

249

1

S → C in bladder cancer, cervical cancer, PLSD-SD and TD; type 1.

VAR_004149

Natural variant

250

1

P → R in MNKS; also some individuals with autosomal dominant congenital sensorineural deafness without craniosynostosis. dbSNP rs4647924.

VAR_004150

Natural variant

322

1

E → K in colorectal cancer.

VAR_018388

Natural variant

338

1

T → M

VAR_042209

Natural variant

370

1

G → C in bladder cancer, keratinocytic non-epidermolytic nevus and TD; type 1.

VAR_004151

Natural variant

371

1

S → C in TD; type 1.

VAR_004152

Natural variant

373

1

Y → C in PLSD-SD and TD; type 1.

VAR_004153

Natural variant

375

1

G → C in ACH.

VAR_004154

Natural variant

380

1

G → R in keratinocytic non-epidermolytic nevus and ACH; results in constitutive activation; very common mutation. dbSNP rs28931614.

VAR_004155

Natural variant

384

1

F → L: dbSNP rs17881656.

VAR_022168

Natural variant

391

1

A → E in Crouzon syndrome with acanthosis nigricans. dbSNP rs28931615.

VAR_004156

Natural variant

441

1

A → T: dbSNP rs17884368.

VAR_022169

Natural variant

513

1

D → N in LADDS.

VAR_029887

Natural variant

538

1

I → V in hypochondroplasia.

VAR_004157

Natural variant

540

1

N → K in hypochondroplasia.

VAR_004158

Natural variant

540

1

N → S in hypochondroplasia; mild.

VAR_018389

Natural variant

540

1

N → T in hypochondroplasia.

VAR_004159

Natural variant

621

1

R → H in CATSHL syndrome.

VAR_029108

Natural variant

646

1

D → N

VAR_042210

Natural variant

650

1

K → E in TD and bladder cancer samples; bladder transitional cell carcinoma; somatic mutation.

VAR_004160

Natural variant

650

1

K → M in ACH and TD; type 1.

VAR_004161

Natural variant

650

1

K → Q in hypochondroplasia and bladder cancer; in hypochondroplasia the form is milder than that seen in individuals with the K-540 or M-650 mutations.

VAR_018390

Natural variant

717

1

A → T: dbSNP rs17882190.

VAR_022170

Natural variant

726

1

I → F: dbSNP rs17880763.

VAR_022171

Experimental info

Sequence conflict

395

1

L → V in AAA58470. Ref.4

Secondary structure

1

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806

Helix Strand Turn

Details...

Beta strand

163 – 167

5

Beta strand

172 – 175

4

Beta strand

185 – 187

3

Turn

208 – 211

4

Beta strand

212 – 215

4

Helix

220 – 222

3

Beta strand

226 – 232

7

Beta strand

235 – 246

12

Beta strand

263 – 268

6

Beta strand

271 – 273

3

Beta strand

283 – 289

7

Helix

293 – 295

3

Beta strand

302 – 304

3

Beta strand

324 – 326

3

Beta strand

335 – 345

11

Beta strand

348 – 357

10

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (IIIc) [UniParc]. Last modified August 1, 1991. Version 1. Checksum: BC5EA75EA46F447E	FASTA	806	87,710
	10 20 30 40 50 60 MGAPACALAL CVAVAIVAGA SSESLGTEQR VVGRAAEVPG PEPGQQEQLV FGSGDAVELS 70 80 90 100 110 120 CPPPGGGPMG PTVWVKDGTG LVPSERVLVG PQRLQVLNAS HEDSGAYSCR QRLTQRVLCH 130 140 150 160 170 180 FSVRVTDAPS SGDDEDGEDE AEDTGVDTGA PYWTRPERMD KKLLAVPAAN TVRFRCPAAG 190 200 210 220 230 240 NPTPSISWLK NGREFRGEHR IGGIKLRHQQ WSLVMESVVP SDRGNYTCVV ENKFGSIRQT 250 260 270 280 290 300 YTLDVLERSP HRPILQAGLP ANQTAVLGSD VEFHCKVYSD AQPHIQWLKH VEVNGSKVGP 310 320 330 340 350 360 DGTPYVTVLK TAGANTTDKE LEVLSLHNVT FEDAGEYTCL AGNSIGFSHH SAWLVVLPAE 370 380 390 400 410 420 EELVEADEAG SVYAGILSYG VGFFLFILVV AAVTLCRLRS PPKKGLGSPT VHKISRFPLK 430 440 450 460 470 480 RQVSLESNAS MSSNTPLVRI ARLSSGEGPT LANVSELELP ADPKWELSRA RLTLGKPLGE 490 500 510 520 530 540 GCFGQVVMAE AIGIDKDRAA KPVTVAVKML KDDATDKDLS DLV