Fibroblast growth factor receptor 3
Also known as: FGFR3, JTK4
Function
Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. 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. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling.
Classification
- Family (Pfam)
- PF21165 FGFR3_TM, PF07679 I-set, PF13927 Ig_3, PF07714 PK_Tyr_Ser-Thr
- InterPro
- FGF_rcpt_fam, Ig-like_dom, Ig-like_dom_sf, Ig-like_fold, Ig_I-set, Ig_sub, Ig_sub2, Kinase-like_dom_sf, Prot_kinase_dom, Protein_kinase_ATP_BS, RTK, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_AS, Tyr_kinase_cat_dom
- Functional cluster
- Immunoglobulin-Domain Cell Adhesion Proteins
Experimental structures · PDB · 13
- 1RY7 X-ray 3.20A
- 2LZL NMR
- 4K33 X-ray 2.34A
- 6LVM X-ray 2.53A
- 6PNX X-ray 2.20A
- 7DHL X-ray 2.57A
- 7YSU EM 3.20A
- 8UDT X-ray 2.83A
- 8UDU X-ray 1.74A
- 8UDV X-ray 2.35A
- 9CD7 X-ray 2.53A
- 9D1X X-ray 1.60A
- … and 1 more
A predicted model is available from AlphaFold.
Gene Ontology · 30
- GO:0005783 endoplasmic reticulum
- GO:0005576 extracellular region
- GO:0005794 Golgi apparatus
- GO:0005886 plasma membrane
- GO:0043235 receptor complex
- GO:0030133 transport vesicle
- GO:0005524 ATP binding
- GO:0017134 fibroblast growth factor binding
- GO:0005007 fibroblast growth factor receptor activity
- GO:0042802 identical protein binding
- GO:0004713 protein tyrosine kinase activity
- GO:0070977 bone maturation
- GO:0030282 bone mineralization
- GO:0060349 bone morphogenesis
- GO:0007259 cell surface receptor signaling pathway via JAK-STAT
- GO:0002062 chondrocyte differentiation
- GO:0035988 chondrocyte proliferation
- GO:0003416 endochondral bone growth
- GO:0001958 endochondral ossification
- GO:1902178 fibroblast growth factor receptor apoptotic signaling pathway
- GO:0008543 fibroblast growth factor receptor signaling pathway
- GO:0000165 MAPK cascade
- GO:0048640 negative regulation of developmental growth
- GO:0008284 positive regulation of cell population proliferation
- GO:0070374 positive regulation of ERK1 and ERK2 cascade
- GO:0043410 positive regulation of MAPK cascade
- GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
- GO:0010518 positive regulation of phospholipase activity
- GO:0042531 positive regulation of tyrosine phosphorylation of STAT protein
- GO:0001501 skeletal system development
Disease associations
- achondroplasia MONDO:0007037
- urinary bladder cancer MONDO:0001187
- hypochondroplasia MONDO:0007793
- nevus, epidermal MONDO:0008093
- seborrheic keratosis MONDO:0008420
- thanatophoric dysplasia type 1 MONDO:0008546
- thanatophoric dysplasia type 2 MONDO:0008547
- plasma cell myeloma MONDO:0009693
- testicular germ cell tumor MONDO:0010108
- Muenke syndrome MONDO:0011274
- cervical cancer MONDO:0002974
- camptodactyly-tall stature-scoliosis-hearing loss syndrome MONDO:0012504
- Crouzon syndrome-acanthosis nigricans syndrome MONDO:0012833
- severe achondroplasia-developmental delay-acanthosis nigricans syndrome MONDO:0014658
- lacrimoauriculodentodigital syndrome 2 MONDO:0859577
Drugs targeting this protein · 21
- PAZOPANIB HYDROCHLORIDE inhibitor
- INFIGRATINIB PHOSPHATE inhibitor
- INFIGRATINIB inhibitor
- MASITINIB inhibitor
- BRIVANIB ALANINATE inhibitor
- ORANTINIB inhibitor
- NINTEDANIB ESYLATE inhibitor
- FEXAGRATINIB inhibitor
- ERDAFITINIB inhibitor
- E-7090 inhibitor
- FUTIBATINIB inhibitor
- BRIVANIB inhibitor
- LY-2874455 inhibitor
- FGFR INHIBITOR DEBIO 1347 inhibitor
- ROGARATINIB inhibitor
- DERAZANTINIB inhibitor
- PEMIGATINIB inhibitor
- ENMD-2076 inhibitor
- DOVITINIB inhibitor
- ENMD-981693 inhibitor
- XL-999 inhibitor
Neighborhood · nearest proteins
Related proteins · sequence + function similarity
- Fibroblast growth factor receptor 3 0.99
- Fibroblast growth factor receptor 1 0.93
- Fibroblast growth factor receptor 1 0.93
- Fibroblast growth factor receptor 1 0.92
- Fibroblast growth factor receptor 3 0.92
- Fibroblast growth factor receptor 3 0.91
- Fibroblast growth factor receptor 4 0.91
- Fibroblast growth factor receptor 4 0.90
- Fibroblast growth factor receptor 1 0.90
- Fibroblast growth factor receptor 3 0.89
- Fibroblast growth factor receptor 2 0.88
- Fibroblast growth factor receptor 1 0.88
Co-cited proteins · studied together in the literature
- Signal transducer and activator of transcription 5A 1 shared papers
- Fibroblast growth factor receptor 4 7 shared papers
- Fibroblast growth factor 1 5 shared papers
- Fibroblast growth factor 10 3 shared papers
- Fibroblast growth factor receptor 2 7 shared papers
- 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 3 shared papers
- Signal transducer and activator of transcription 1 2 shared papers
- Signal transducer and activator of transcription 1-alpha/beta 3 shared papers
- Suppressor of cytokine signaling 3 1 shared papers
- Fibroblast growth factor receptor 4 1 shared papers
- E3 ubiquitin-protein ligase CBL 2 shared papers
- Suppressor of cytokine signaling 1 1 shared papers
Literature · 63 cited papers
- Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
- Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer · 2010
- Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat. Genet. · 2009
- A novel interaction between fibroblast growth factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase: activation-dependent regulation of ERK by p85 in multiple myeloma cells. Hum. Mol. Genet. · 2009
- Analysis of STAT1 activation by six FGFR3 mutants associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3 signaling in cartilage. PLoS ONE · 2008
- FGFR3-related dwarfism and cell signaling. J. Bone Miner. Metab. · 2009
- A quantitative atlas of mitotic phosphorylation. Proc. Natl. Acad. Sci. U.S.A. · 2008
- Crouzon with acanthosis nigricans. Further delineation of the syndrome. Clin. Genet. · 2007
- Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. · 2007
- Sustained phosphorylation of mutated FGFR3 is a crucial feature of genetic dwarfism and induces apoptosis in the ATDC5 chondrogenic cell line via PLCgamma-activated STAT1. Bone · 2007
- The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor. FEBS J. · 2007
- Patterns of somatic mutation in human cancer genomes. Nature · 2007
- … and 51 more in the literature graph