The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development.
Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events.
This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.
View original pathway at:Reactome.
Capelletti M, Dodge ME, Ercan D, Hammerman PS, Park SI, Kim J, Sasaki H, Jablons DM, Lipson D, Young L, Stephens PJ, Miller VA, Lindeman NI, Munir KJ, Richards WG, Jänne PA.; ''Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma.''; PubMedEurope PMCScholia
Ornitz DM, Marie PJ.; ''FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease.''; PubMedEurope PMCScholia
Mason JM, Morrison DJ, Bassit B, Dimri M, Band H, Licht JD, Gross I.; ''Tyrosine phosphorylation of Sprouty proteins regulates their ability to inhibit growth factor signaling: a dual feedback loop.''; PubMedEurope PMCScholia
DaSilva J, Xu L, Kim HJ, Miller WT, Bar-Sagi D.; ''Regulation of sprouty stability by Mnk1-dependent phosphorylation.''; PubMedEurope PMCScholia
Zhang Y, Hiraishi Y, Wang H, Sumi KS, Hayashido Y, Toratani S, Kan M, Sato JD, Okamoto T.; ''Constitutive activating mutation of the FGFR3b in oral squamous cell carcinomas.''; PubMedEurope PMCScholia
Smit L, de Vries-Smits AM, Bos JL, Borst J.; ''B cell antigen receptor stimulation induces formation of a Shc-Grb2 complex containing multiple tyrosine-phosphorylated proteins.''; PubMedEurope PMCScholia
Parker BC, Engels M, Annala M, Zhang W.; ''Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours.''; PubMedEurope PMCScholia
Turjanski AG, Vaqué JP, Gutkind JS.; ''MAP kinases and the control of nuclear events.''; PubMedEurope PMCScholia
Kato K, Jeanneau C, Tarp MA, Benet-Pagès A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H.; ''Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation.''; PubMedEurope PMCScholia
Tomlinson DC, Baldo O, Harnden P, Knowles MA.; ''FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer.''; PubMedEurope PMCScholia
Beenken A, Mohammadi M.; ''The FGF family: biology, pathophysiology and therapy.''; PubMedEurope PMCScholia
Trudel S, Stewart AK, Rom E, Wei E, Li ZH, Kotzer S, Chumakov I, Singer Y, Chang H, Liang SB, Yayon A.; ''The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells.''; PubMedEurope PMCScholia
Rubin C, Litvak V, Medvedovsky H, Zwang Y, Lev S, Yarden Y.; ''Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops.''; PubMedEurope PMCScholia
Tavormina PL, Rimoin DL, Cohn DH, Zhu YZ, Shiang R, Wasmuth JJ.; ''Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I.''; PubMedEurope PMCScholia
Intini D, Baldini L, Fabris S, Lombardi L, Ciceri G, Maiolo AT, Neri A.; ''Analysis of FGFR3 gene mutations in multiple myeloma patients with t(4;14).''; PubMedEurope PMCScholia
Bernard-Pierrot I, Gruel N, Stransky N, Vincent-Salomon A, Reyal F, Raynal V, Vallot C, Pierron G, Radvanyi F, Delattre O.; ''Characterization of the recurrent 8p11-12 amplicon identifies PPAPDC1B, a phosphatase protein, as a new therapeutic target in breast cancer.''; PubMedEurope PMCScholia
Gotoh N.; ''Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins.''; PubMedEurope PMCScholia
Webster MK, Donoghue DJ.; ''Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia.''; PubMedEurope PMCScholia
Krejci P, Murakami S, Prochazkova J, Trantirek L, Chlebova K, Ouyang Z, Aklian A, Smutny J, Bryja V, Kozubik A, Wilcox WR.; ''NF449 is a novel inhibitor of fibroblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myeloma cells.''; PubMedEurope PMCScholia
Curto M, Frankel P, Carrero A, Foster DA.; ''Novel recruitment of Shc, Grb2, and Sos by fibroblast growth factor receptor-1 in v-Src-transformed cells.''; PubMedEurope PMCScholia
Agazie YM, Movilla N, Ischenko I, Hayman MJ.; ''The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3.''; PubMedEurope PMCScholia
Singh P, Thomas GE, Gireesh KK, Manna TK.; ''TACC3 protein regulates microtubule nucleation by affecting γ-tubulin ring complexes.''; PubMedEurope PMCScholia
Carpenter G, Ji Q.; ''Phospholipase C-gamma as a signal-transducing element.''; PubMedEurope PMCScholia
Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMedEurope PMCScholia
Wellbrock C, Karasarides M, Marais R.; ''The RAF proteins take centre stage.''; PubMedEurope PMCScholia
Sibley K, Cuthbert-Heavens D, Knowles MA.; ''Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma.''; PubMedEurope PMCScholia
Williams EJ, Furness J, Walsh FS, Doherty P.; ''Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin.''; PubMedEurope PMCScholia
Lindgren D, Liedberg F, Andersson A, Chebil G, Gudjonsson S, Borg A, Månsson W, Fioretos T, Höglund M.; ''Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q.''; PubMedEurope PMCScholia
Chou A, Dekker N, Jordan RC.; ''Identification of novel fibroblast growth factor receptor 3 gene mutations in actinic cheilitis and squamous cell carcinoma of the lip.''; PubMedEurope PMCScholia
Hadari YR, Gotoh N, Kouhara H, Lax I, Schlessinger J.; ''Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways.''; PubMedEurope PMCScholia
Brown MD, Sacks DB.; ''Protein scaffolds in MAP kinase signalling.''; PubMedEurope PMCScholia
Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I.; ''Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins.''; PubMedEurope PMCScholia
Soverini S, Terragna C, Testoni N, Ruggeri D, Tosi P, Zamagni E, Cellini C, Cavo M, Baccarani M, Tura S, Martinelli G.; ''Novel mutation and RNA splice variant of fibroblast growth factor receptor 3 in multiple myeloma patients at diagnosis.''; PubMedEurope PMCScholia
Dailey L, Ambrosetti D, Mansukhani A, Basilico C.; ''Mechanisms underlying differential responses to FGF signaling.''; PubMedEurope PMCScholia
Xu H, Lee KW, Goldfarb M.; ''Novel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adapter proteins.''; PubMedEurope PMCScholia
Roskoski R.; ''RAF protein-serine/threonine kinases: structure and regulation.''; PubMedEurope PMCScholia
Mohammadi M, Olsen SK, Ibrahimi OA.; ''Structural basis for fibroblast growth factor receptor activation.''; PubMedEurope PMCScholia
Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D.; ''Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2.''; PubMedEurope PMCScholia
Mohammadi M, Dionne CA, Li W, Li N, Spivak T, Honegger AM, Jaye M, Schlessinger J.; ''Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis.''; PubMedEurope PMCScholia
Yuan L, Liu ZH, Lin ZR, Xu LH, Zhong Q, Zeng MS.; ''Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma.''; PubMedEurope PMCScholia
Lao DH, Yusoff P, Chandramouli S, Philp RJ, Fong CW, Jackson RA, Saw TY, Yu CY, Guy GR.; ''Direct binding of PP2A to Sprouty2 and phosphorylation changes are a prerequisite for ERK inhibition downstream of fibroblast growth factor receptor stimulation.''; PubMedEurope PMCScholia
Zhou W, Feng X, Wu Y, Benge J, Zhang Z, Chen Z.; ''FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway.''; PubMedEurope PMCScholia
Goriely A, Hansen RM, Taylor IB, Olesen IA, Jacobsen GK, McGowan SJ, Pfeifer SP, McVean GA, Rajpert-De Meyts E, Wilkie AO.; ''Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors.''; PubMedEurope PMCScholia
Hatch NE, Hudson M, Seto ML, Cunningham ML, Bothwell M.; ''Intracellular retention, degradation, and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndrome-associated FGFR2C278F.''; PubMedEurope PMCScholia
Schlessinger J.; ''Common and distinct elements in cellular signaling via EGF and FGF receptors.''; PubMedEurope PMCScholia
di Martino E, L'Hôte CG, Kennedy W, Tomlinson DC, Knowles MA.; ''Mutant fibroblast growth factor receptor 3 induces intracellular signaling and cellular transformation in a cell type- and mutation-specific manner.''; PubMedEurope PMCScholia
Hart KC, Robertson SC, Donoghue DJ.; ''Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation.''; PubMedEurope PMCScholia
d'Avis PY, Robertson SC, Meyer AN, Bardwell WM, Webster MK, Donoghue DJ.; ''Constitutive activation of fibroblast growth factor receptor 3 by mutations responsible for the lethal skeletal dysplasia thanatophoric dysplasia type I.''; PubMedEurope PMCScholia
Minegishi Y, Iwanari H, Mochizuki Y, Horii T, Hoshino T, Kodama T, Hamakubo T, Gotoh N.; ''Prominent expression of FRS2beta protein in neural cells and its association with intracellular vesicles.''; PubMedEurope PMCScholia
Burgess SG, Peset I, Joseph N, Cavazza T, Vernos I, Pfuhl M, Gergely F, Bayliss R.; ''Aurora-A-Dependent Control of TACC3 Influences the Rate of Mitotic Spindle Assembly.''; PubMedEurope PMCScholia
Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMedEurope PMCScholia
Schüller AC, Ahmed Z, Levitt JA, Suen KM, Suhling K, Ladbury JE.; ''Indirect recruitment of the signalling adaptor Shc to the fibroblast growth factor receptor 2 (FGFR2).''; PubMedEurope PMCScholia
Brady SC, Coleman ML, Munro J, Feller SM, Morrice NA, Olson MF.; ''Sprouty2 association with B-Raf is regulated by phosphorylation and kinase conformation.''; PubMedEurope PMCScholia
Li E, You M, Hristova K.; ''FGFR3 dimer stabilization due to a single amino acid pathogenic mutation.''; PubMedEurope PMCScholia
Wesche J, Haglund K, Haugsten EM.; ''Fibroblast growth factors and their receptors in cancer.''; PubMedEurope PMCScholia
Mohammadi M, Honegger AM, Rotin D, Fischer R, Bellot F, Li W, Dionne CA, Jaye M, Rubinstein M, Schlessinger J.; ''A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1.''; PubMedEurope PMCScholia
Wang R, Wang L, Li Y, Hu H, Shen L, Shen X, Pan Y, Ye T, Zhang Y, Luo X, Zhang Y, Pan B, Li B, Li H, Zhang J, Pao W, Ji H, Sun Y, Chen H.; ''FGFR1/3 tyrosine kinase fusions define a unique molecular subtype of non-small cell lung cancer.''; PubMedEurope PMCScholia
Trudel S, Ely S, Farooqi Y, Affer M, Robbiani DF, Chesi M, Bergsagel PL.; ''Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma.''; PubMedEurope PMCScholia
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMedEurope PMCScholia
Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, Liu EM, Reichel J, Porrati P, Pellegatta S, Qiu K, Gao Z, Ceccarelli M, Riccardi R, Brat DJ, Guha A, Aldape K, Golfinos JG, Zagzag D, Mikkelsen T, Finocchiaro G, Lasorella A, Rabadan R, Iavarone A.; ''Transforming fusions of FGFR and TACC genes in human glioblastoma.''; PubMedEurope PMCScholia
Yigzaw Y, Cartin L, Pierre S, Scholich K, Patel TB.; ''The C terminus of sprouty is important for modulation of cellular migration and proliferation.''; PubMedEurope PMCScholia
Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N, Schlessinger J, Lax I.; ''FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors.''; PubMedEurope PMCScholia
Lim J, Wong ES, Ong SH, Yusoff P, Low BC, Guy GR.; ''Sprouty proteins are targeted to membrane ruffles upon growth factor receptor tyrosine kinase activation. Identification of a novel translocation domain.''; PubMedEurope PMCScholia
Ronchetti D, Greco A, Compasso S, Colombo G, Dell'Era P, Otsuki T, Lombardi L, Neri A.; ''Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations.''; PubMedEurope PMCScholia
Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J.; ''A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway.''; PubMedEurope PMCScholia
Li X, Brunton VG, Burgar HR, Wheldon LM, Heath JK.; ''FRS2-dependent SRC activation is required for fibroblast growth factor receptor-induced phosphorylation of Sprouty and suppression of ERK activity.''; PubMedEurope PMCScholia
Hanafusa H, Torii S, Yasunaga T, Matsumoto K, Nishida E.; ''Shp2, an SH2-containing protein-tyrosine phosphatase, positively regulates receptor tyrosine kinase signaling by dephosphorylating and inactivating the inhibitor Sprouty.''; PubMedEurope PMCScholia
Hernández S, de Muga S, Agell L, Juanpere N, Esgueva R, Lorente JA, Mojal S, Serrano S, Lloreta J.; ''FGFR3 mutations in prostate cancer: association with low-grade tumors.''; PubMedEurope PMCScholia
Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, Israel J, Rosengren SS, Webster MK, Donoghue DJ, Francomano CA.; ''Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype.''; PubMedEurope PMCScholia
Wu Y, Chen Z, Ullrich A.; ''EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2.''; PubMedEurope PMCScholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMedEurope PMCScholia
Kanai M, Göke M, Tsunekawa S, Podolsky DK.; ''Signal transduction pathway of human fibroblast growth factor receptor 3. Identification of a novel 66-kDa phosphoprotein.''; PubMedEurope PMCScholia
Trudel S, Li ZH, Wei E, Wiesmann M, Chang H, Chen C, Reece D, Heise C, Stewart AK.; ''CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma.''; PubMedEurope PMCScholia
Klint P, Kanda S, Claesson-Welsh L.; ''Shc and a novel 89-kDa component couple to the Grb2-Sos complex in fibroblast growth factor-2-stimulated cells.''; PubMedEurope PMCScholia
Ong SH, Goh KC, Lim YP, Low BC, Klint P, Claesson-Welsh L, Cao X, Tan YH, Guy GR.; ''Suc1-associated neurotrophic factor target (SNT) protein is a major FGF-stimulated tyrosine phosphorylated 90-kDa protein which binds to the SH2 domain of GRB2.''; PubMedEurope PMCScholia
Mohammadi M, Dikic I, Sorokin A, Burgess WH, Jaye M, Schlessinger J.; ''Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction.''; PubMedEurope PMCScholia
van Rhijn BW, van Tilborg AA, Lurkin I, Bonaventure J, de Vries A, Thiery JP, van der Kwast TH, Zwarthoff EC, Radvanyi F.; ''Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders.''; PubMedEurope PMCScholia
Carter EP, Fearon AE, Grose RP.; ''Careless talk costs lives: fibroblast growth factor receptor signalling and the consequences of pathway malfunction.''; PubMedEurope PMCScholia
Chesi M, Nardini E, Brents LA, Schröck E, Ried T, Kuehl WM, Bergsagel PL.; ''Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3.''; PubMedEurope PMCScholia
Meyers GA, Orlow SJ, Munro IR, Przylepa KA, Jabs EW.; ''Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans.''; PubMedEurope PMCScholia
Otsuki T, Yamada O, Yata K, Sakaguchi H, Kurebayashi J, Nakazawa N, Taniwaki M, Yawata Y, Ueki A.; ''Expression of fibroblast growth factor and FGF-receptor family genes in human myeloma cells, including lines possessing t(4;14)(q16.3;q32. 3) and FGFR3 translocation.''; PubMedEurope PMCScholia
Webster MK, Donoghue DJ.; ''FGFR activation in skeletal disorders: too much of a good thing.''; PubMedEurope PMCScholia
Hadari YR, Kouhara H, Lax I, Schlessinger J.; ''Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation.''; PubMedEurope PMCScholia
Lim J, Yusoff P, Wong ES, Chandramouli S, Lao DH, Fong CW, Guy GR.; ''The cysteine-rich sprouty translocation domain targets mitogen-activated protein kinase inhibitory proteins to phosphatidylinositol 4,5-bisphosphate in plasma membranes.''; PubMedEurope PMCScholia
Paterson JL, Li Z, Wen XY, Masih-Khan E, Chang H, Pollett JB, Trudel S, Stewart AK.; ''Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma.''; PubMedEurope PMCScholia
Wong ES, Lim J, Low BC, Chen Q, Guy GR.; ''Evidence for direct interaction between Sprouty and Cbl.''; PubMedEurope PMCScholia
Carneiro BA, Elvin JA, Kamath SD, Ali SM, Paintal AS, Restrepo A, Berry E, Giles FJ, Johnson ML.; ''FGFR3-TACC3: A novel gene fusion in cervical cancer.''; PubMedEurope PMCScholia
Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMedEurope PMCScholia
Ibrahimi OA, Zhang F, Eliseenkova AV, Itoh N, Linhardt RJ, Mohammadi M.; ''Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities.''; PubMedEurope PMCScholia
Yusoff P, Lao DH, Ong SH, Wong ES, Lim J, Lo TL, Leong HF, Fong CW, Guy GR.; ''Sprouty2 inhibits the Ras/MAP kinase pathway by inhibiting the activation of Raf.''; PubMedEurope PMCScholia
Lao DH, Chandramouli S, Yusoff P, Fong CW, Saw TY, Tai LP, Yu CY, Leong HF, Guy GR.; ''A Src homology 3-binding sequence on the C terminus of Sprouty2 is necessary for inhibition of the Ras/ERK pathway downstream of fibroblast growth factor receptor stimulation.''; PubMedEurope PMCScholia
Tavormina PL, Shiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ.; ''Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3.''; PubMedEurope PMCScholia
Dance M, Montagner A, Salles JP, Yart A, Raynal P.; ''The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway.''; PubMedEurope PMCScholia
Cappellen D, De Oliveira C, Ricol D, de Medina S, Bourdin J, Sastre-Garau X, Chopin D, Thiery JP, Radvanyi F.; ''Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas.''; PubMedEurope PMCScholia
Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I, Szabo J, Jiang W, Jiang W, Jabs EW, Wilcox WR, Wasmuth JJ, Donoghue DJ, Thompson LM, Francomano CA.; ''A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene.''; PubMedEurope PMCScholia
Naski MC, Wang Q, Xu J, Ornitz DM.; ''Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia.''; PubMedEurope PMCScholia
Hall AB, Jura N, DaSilva J, Jang YJ, Gong D, Bar-Sagi D.; ''hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl.''; PubMedEurope PMCScholia
Impagnatiello MA, Weitzer S, Gannon G, Compagni A, Cotten M, Christofori G.; ''Mammalian sprouty-1 and -2 are membrane-anchored phosphoprotein inhibitors of growth factor signaling in endothelial cells.''; PubMedEurope PMCScholia
Parker BC, Annala MJ, Cogdell DE, Granberg KJ, Sun Y, Ji P, Li X, Gumin J, Zheng H, Hu L, Yli-Harja O, Haapasalo H, Visakorpi T, Liu X, Liu CG, Sawaya R, Fuller GN, Chen K, Lang FF, Nykter M, Zhang W.; ''The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma.''; PubMedEurope PMCScholia
Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM.; ''Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family.''; PubMedEurope PMCScholia
Ibrahimi OA, Zhang F, Eliseenkova AV, Linhardt RJ, Mohammadi M.; ''Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity.''; PubMedEurope PMCScholia
Qing J, Du X, Chen Y, Chan P, Li H, Wu P, Marsters S, Stawicki S, Tien J, Totpal K, Ross S, Stinson S, Dornan D, French D, Wang QR, Stephan JP, Wu Y, Wiesmann C, Ashkenazi A.; ''Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice.''; PubMedEurope PMCScholia
Gotoh N, Laks S, Nakashima M, Lax I, Schlessinger J.; ''FRS2 family docking proteins with overlapping roles in activation of MAP kinase have distinct spatial-temporal patterns of expression of their transcripts.''; PubMedEurope PMCScholia
Onishi-Haraikawa Y, Funaki M, Gotoh N, Shibuya M, Inukai K, Katagiri H, Fukushima Y, Anai M, Ogihara T, Sakoda H, Ono H, Kikuchi M, Oka Y, Asano T.; ''Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein.''; PubMedEurope PMCScholia
McKay MM, Morrison DK.; ''Integrating signals from RTKs to ERK/MAPK.''; PubMedEurope PMCScholia
Chesi M, Brents LA, Ely SA, Bais C, Robbiani DF, Mesri EA, Kuehl WM, Bergsagel PL.; ''Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma.''; PubMedEurope PMCScholia
Rubin C, Zwang Y, Vaisman N, Ron D, Yarden Y.; ''Phosphorylation of carboxyl-terminal tyrosines modulates the specificity of Sprouty-2 inhibition of different signaling pathways.''; PubMedEurope PMCScholia
Rousseau F, el Ghouzzi V, Delezoide AL, Legeai-Mallet L, Le Merrer M, Munnich A, Bonaventure J.; ''Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1).''; PubMedEurope PMCScholia
Ahmed Z, Schüller AC, Suhling K, Tregidgo C, Ladbury JE.; ''Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signalling.''; PubMedEurope PMCScholia
Roberts PJ, Der CJ.; ''Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.''; PubMedEurope PMCScholia
Williams SV, Hurst CD, Knowles MA.; ''Oncogenic FGFR3 gene fusions in bladder cancer.''; PubMedEurope PMCScholia
Avet-Loiseau H, Li JY, Facon T, Brigaudeau C, Morineau N, Maloisel F, Rapp MJ, Talmant P, Trimoreau F, Jaccard A, Harousseau JL, Bataille R.; ''High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies.''; PubMedEurope PMCScholia
Wong A, Lamothe B, Lee A, Schlessinger J, Lax I.; ''FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl.''; PubMedEurope PMCScholia
Cross MJ, Hodgkin MN, Roberts S, Landgren E, Wakelam MJ, Claesson-Welsh L.; ''Tyrosine 766 in the fibroblast growth factor receptor-1 is required for FGF-stimulation of phospholipase C, phospholipase D, phospholipase A(2), phosphoinositide 3-kinase and cytoskeletal reorganisation in porcine aortic endothelial cells.''; PubMedEurope PMCScholia
Burke D, Wilkes D, Blundell TL, Malcolm S.; ''Fibroblast growth factor receptors: lessons from the genes.''; PubMedEurope PMCScholia
Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, Lonigro RJ, Vats P, Wang R, Lin SF, Cheng AJ, Kunju LP, Siddiqui J, Tomlins SA, Wyngaard P, Sadis S, Roychowdhury S, Hussain MH, Feng FY, Zalupski MM, Talpaz M, Pienta KJ, Rhodes DR, Robinson DR, Chinnaiyan AM.; ''Identification of targetable FGFR gene fusions in diverse cancers.''; PubMedEurope PMCScholia
Chen J, Lee BH, Williams IR, Kutok JL, Mitsiades CS, Duclos N, Cohen S, Adelsperger J, Okabe R, Coburn A, Moore S, Huntly BJ, Fabbro D, Anderson KC, Griffin JD, Gilliland DG.; ''FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies.''; PubMedEurope PMCScholia
Grand EK, Chase AJ, Heath C, Rahemtulla A, Cross NC.; ''Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074.''; PubMedEurope PMCScholia
Cantwell-Dorris ER, O'Leary JJ, Sheils OM.; ''BRAFV600E: implications for carcinogenesis and molecular therapy.''; PubMedEurope PMCScholia
Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMedEurope PMCScholia
Reardon W, Wilkes D, Rutland P, Pulleyn LJ, Malcolm S, Dean JC, Evans RD, Jones BM, Hayward R, Hall CM, Nevin NC, Baraister M, Winter RM.; ''Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis.''; PubMedEurope PMCScholia
Patterson RL, van Rossum DB, Nikolaidis N, Gill DL, Snyder SH.; ''Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.''; PubMedEurope PMCScholia
Ong SH, Lim YP, Low BC, Guy GR.; ''SHP2 associates directly with tyrosine phosphorylated p90 (SNT) protein in FGF-stimulated cells.''; PubMedEurope PMCScholia
Eswarakumar VP, Lax I, Schlessinger J.; ''Cellular signaling by fibroblast growth factor receptors.''; PubMedEurope PMCScholia
Rousseau F, Saugier P, Le Merrer M, Munnich A, Delezoide AL, Maroteaux P, Bonaventure J, Narcy F, Sanak M.; ''Stop codon FGFR3 mutations in thanatophoric dwarfism type 1.''; PubMedEurope PMCScholia
Bellus GA, Gaudenz K, Zackai EH, Clarke LA, Szabo J, Francomano CA, Muenke M.; ''Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes.''; PubMedEurope PMCScholia
Webster MK, D'Avis PY, Robertson SC, Donoghue DJ.; ''Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II.''; PubMedEurope PMCScholia
Wang JK, Gao G, Goldfarb M.; ''Fibroblast growth factor receptors have different signaling and mitogenic potentials.''; PubMedEurope PMCScholia
Fong CW, Leong HF, Wong ES, Lim J, Yusoff P, Guy GR.; ''Tyrosine phosphorylation of Sprouty2 enhances its interaction with c-Cbl and is crucial for its function.''; PubMedEurope PMCScholia
Reddy PL, Grewal RP.; ''The G1138A mutation rate in the fibroblast growth factor receptor 3 (FGFR3) gene is increased in cells carrying the t (4; 14) translocation.''; PubMedEurope PMCScholia
Li Z, Zhu YX, Plowright EE, Bergsagel PL, Chesi M, Patterson B, Hawley TS, Hawley RG, Stewart AK.; ''The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells.''; PubMedEurope PMCScholia
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR.; ''Patterns of somatic mutation in human cancer genomes.''; PubMedEurope PMCScholia
Adar R, Monsonego-Ornan E, David P, Yayon A.; ''Differential activation of cysteine-substitution mutants of fibroblast growth factor receptor 3 is determined by cysteine localization.''; PubMedEurope PMCScholia
Lax I, Wong A, Lamothe B, Lee A, Frost A, Hawes J, Schlessinger J.; ''The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors.''; PubMedEurope PMCScholia
Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMedEurope PMCScholia
AZD4547 (Astra Zeneca) is a pan-FGFR inhibitor in Phase I clinical trials for patients with advanced gastric cancer (NCT01457846) and for patient with advanced solid tumors with or without amplified FGFR1 or 2 (NCT00979134) and in Phase I/II trials for breast cancer patients with FGFR1 amplifications (NCT01202591).
A pan-FGFR ATP-competitive inhibitor that is in phase I clinical trials for advanced solid malignancies with amplification or activation of FGFR1 and 2 or activation of FGFR3 (NCT01004224).
Note that residue G697C is numbered according to the FGFR3c isoform, (UniProt 22607-1) and actually corresponds to G699C in the FGFR3b isoform (Uniprot 22607-2).
Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
The phospho-tyrosine positions for FRS2-beta were inferred by similarity to the analogous positions in FRS2-alpha. Five out of six tyrosine positions in alpha are present in beta.
Note that residue G697C is numbered according to the FGFR3c isoform, (UniProt 22607-1) and actually corresponds to G699C in the FGFR3b isoform (Uniprot 22607-2).
SPRY2 translocates to the plasma membrane upon activation of cells with FGF, and translocation is required for the inhibition of growth factor-stimulated cell migration, proliferation and differentiation. Translocation may be mediated by interactions with PIP2 in the membrane, palmitoylation of the C-terminal region of SPRY2 and/or interactions with caveolin-1.
Sprouty 2 protein is phosphorylated on tyrosine residue 55. The ability of SRC kinase to catalyze this reaction has been demonstrated with purified proteins in vitro (Li et al. 2004) and in cultured cells with studies of the effects of SRC-family pharmacological inhibitors and of dominant-negative mutant SRC proteins (Mason et al. 2004). SRC kinase also phosphorylates numerous tyrosine residues in the C terminal region of SPRY2 including Y227, in response to FGF but not EGF stimulation.
Some evidence suggests that SPRY2 may exert its negative effect by binding to GRB2 and competing with the GRB2:SOS1 interaction that is required for MAPK activation. SPRY2 phosphorylation at Y55 is stimulated in response to both FGF and EGF, and is required for SPRY2 to act as a negative regulator of FGF signaling. Y55 is not thought to be a GRB2 binding site, however. Instead, phosphorylation at Y55 is thought to cause a conformational change in SPRY2 that reveals a cryptic PXXPXPR GRB2-docking site in the C-terminal of SPRY2. SPRY2 has also been shown to be phosphorylated at multiple tyrosine residues in its C-terminal in response to FGF, but not EGF, stimulation. This phosphorylation, in particular at residue 227, is thought to augment the ability of SPRY2 to inhibit FGF signaling through the MAPK cascade, although the mechanism remains to be elucidated.
The N terminal TKB domain of CBL binds to the phospho-tyrosine 55 of SPRY2, targeting SPRY2 for degradation by the 26S proteasome. Y55 is also a binding site for PP2A, which dephosphorylates numerous serine and threonine residues on SPRY2, allowing a conformational change that may promote a SPRY2:GRB2 interaction and limit the extent of MAPK activation following FGF stimulation.
In unstimulated cells, SPRY2 has been shown to be phosphorylated on multiple serine and threonine residues. In these cells, SPRY2 exists in a complex with the regulatory and catalytic subunits (A and C, respectively) of the serine/threonine phosphatase PP2A. After stimulation with FGF, the catalytic activity of PP2A increases and the phosphatase dephophorylates SPRY at serine 112 and serine 115. This is thought to promote changes in tertiary structure that promote GRB2 binding and phosphorylation of Y55 and Y227.
Some evidence suggests that SPRY2 can exert its negative role on FGF signaling at the level of RAF activation. Hypophosphorylated SPRY2 binds to inactive B-RAF, preventing it from activating ERK signaling. MAPK activation results in phosphorylation of SPRY2 on six serine residues (S7, S42, S111, S120, S140 and S167), and inhibits B-RAF binding. Phosphorylation at S111 and S120 directly affects B-RAF binding while the remaining four sites appear to contribute indirectly. Oncogenic forms of B-RAF such as B-RAF V600E, which adopt active kinase conformations, do not associate with SPRY2, regardless of its phosphorylation status. This suggests that two mechanisms affect the SPRY2:B-RAF interaction: SPRY2 phosphorylation and B-RAF conformation.
PPTN11 (also known as SHP2) may exert its positive effects on MAPK activation in response to FGF stimulation by catalyzing the dephosphorylation of tyrosine resides on SPRY2. This dephosphorylation promotes dissociation of the GRB2/SPRY2 complex and as a consequence stimulates GRB2 association with the activated receptor, leading to sustained MAPK signaling.
The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1.
In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate.
In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate.
The intrinsic protein tyrosine kinase activity of activated FGF receptor 3 catalyzes multiple phosphorylation events, creating a number of binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Based on sequence alignment, FGFR3 contains 6 of the 8 cytoplasmic tyrosine residues identified in FGFR1. Mutagenesis studies highlight the importance of tyrosine residue 724 in signaling mediated by FGFR3, including transformation, PPTN11/SHP2 phosphorylation, and activation of MAPK, PI3K and STAT pathways. These studies also identified a role for the PLCG1-binding tyrosine residue, Y760, in STAT activation, and a potential role for tyrosine 770 as a negative regulator of FGFR3 signaling.
The intrinsic protein tyrosine kinase activity of activated FGF receptor 3 catalyzes multiple phosphorylation events, creating a number of binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Based on sequence alignment, FGFR3 contains 6 of the 8 cytoplasmic tyrosine residues identified in FGFR1. Mutagenesis studies highlight the importance of tyrosine residue 724 in signaling mediated by FGFR3, including transformation, PPTN11/SHP2 phosphorylation, and activation of MAPK, PI3K and STAT pathways. These studies also identified a role for the PLCG1-binding tyrosine residue, Y760, in STAT activation, and a potential role for tyrosine 770 as a negative regulator of FGFR3 signaling.
After high-affinity ligand binding, FGFR3 P250R is believed to undergo trans-autophosphorylation in a manner analogous to the wild-type receptor, although this remains to be experimentally validated (Ibrahimi, 2004a).
FGFR3 P350R is associated with the development of Muenke syndrome, a milder craniosynostotic condition than Apert Syndrome (Bellus, 1996; Reardon, 1997). This mutation, which falls in the highly conserved Ser-Pro dipeptide in the IgII-IgIII linker, has been shown to increase the affinity of the receptor for its natural ligands, particularly for FGF9 (Ibrahimi, 2004a), without expanding the ligand-binding range of the receptor. This difference, compared to the paralogous FGFR2 S252W and P253R mutations, which bind an expanded range of ligands, is thought to account for the milder phenotype of Muenke Syndrome (Yu, 2000; Ibrahimi, 2004a, b).
Although each of FGFR3 R248C, S249C, G370C, S371C and Y373C have been shown to undergo ligand-independent dimerization and receptor autophosphorylation, there is conflicting evidence about which mutants also show increased phosphorylation upon ligand stimulation. Mutants showed elevated levels of ligand-independent MAPK pathway activation and supported expression of an in vivo reporter gene (d'Avis, 1998; Adar, 2009).
Activating mutations in FGFR3 that introduce a mutant cysteine residue to the Ig2-Ig3 linker domain or the extracellular juxtamembrane region have been identified in the lethal neonatal disorder thanatophoric dysplasia (Tavormina, 1995a, b; Rousseau, 1996; reviewed in Webster and Donoghue, 1997; Burke, 1998). The presence of the mutant cysteine residue causes ligand-independent dimerization of the receptor through Cys-mediated intramolecular disulphide bonds and leads to increased biological signaling without changing the intrinsic kinase activity of the receptor (d'Avis, 1998; Adar, 2002). More recently, the same mutations, arising somatically, have been identified in a range of cancers including bladder, prostrate and cervical cancer, as well as in multiple myeloma and head and neck squamous cell carcinoma (reviewed in Wesche, 2011).
Activating point mutations G380R, N540K and K650E/M/N/Q in FGFR3 have been identified in achondroplasia, hypochondroplasia and thanatophoric dysplasia I and II (reviewed in Webster and Donoghue, 1997, Burke, 1998). These mutants, which occur in the transmembrane and the kinase domain, have been shown to undergo ligand-independent dimerization and autophosphorylation when transfected into NIH 3T3 cells, although the extent of constitutive activation varies depending on the precise mutation (Webster and Donoghue, 1996; Webster, 1996; Naski, 1996; Bellus, 2000). In addition, some of the mutants retain the ability to respond to exogenous ligand, while others appear to be completely ligand-independent (Naski, 1996; Goriely, 2009). Interestingly, the extent of kinase activation correlates with the severity of the resulting condition, with the K650M and E mutations associated with thanatophoric dysplasia showing the higher levels of kinase activity than the G380R mutation associated with achondroplasia (Naski, 1996; Bellus, 2000; Goriely, 2009). More recently, these same mutations, along with G382D, N540S, K650T, and G97C, have also been identified in a range of cancers, most notably in bladder cancer and multiple myeloma (Zhang, 2005; Ronchetti, 2001; van Rhijn, 2002; Lindgren, 2006; reveiewed in Wesche, 2011; Greulich and Pollock, 2011).
Activated point mutants in the transmembrane and kinase domains of FGFR3 have been shown to undergo constitutive autophosphorylation in a ligand-independent manner (Naski, 1996; Webster, 1996 and Donoghue, 1996; Webster, 1996; Bellus, 2000; Goriely, 2009). Some of the point mutants, including K650E and G380R, may also be able to further respond after exposure to ligand (Naski, 1996). Dimerization and activation of the FGFR3 transmembrane mutants is thought to occur via the formation of non-native hydrogen bonds that promote intermolecular interactions (Webster and Donoghue 1996), while the kinase domain mutants activate phosphorylation by mimicking conformational changes in the activation loop (Webster, 1996). Mutants with enhanced kinase activity appear to be activated to differing extents that, for the most part, correlate with the severity of the disease phenotype (Webster, 1996; Bellus, 2000; Goriely, 2009), although the results of in vitro kinase assays with immunoprecipitated proteins do not fully recapitulate the pathological consequences of the mutation (Goriely, 2009). K650E has also been shown to transform NIH 3T3 cells (Chesi, 2001).
~15% of multiple myelomas contain translocations that put the FGFR3 gene under the control of the strong IGH locus (Chesi, 1997; Avet-Loiseau, 1998). This translocation results in the overexpresssion of FGFR3 (Chesi, 1997), which leads to aberrant signaling in either a ligand-dependent (Otsuki, 1999; Qing, 2009) or independent fashion (Chesi, 2001). Overexpression of WT FGFR3 results in a low level of FGF-independent MAPK activation, suggesting that overexpression can lead to ligand-independent dimerization; however this response is more pronounced after ligand-stimulation (Chesi, 2001; Qing, 2009). ~5% of multiple myelomas with FGFR3 translocations also contain coding sequence activating mutations (Chesi, 1997; Avet-Loiseau, 1998). These mutations (R248C, Y373C, K650E and K650M) mimic activating mutations seen in bone development disoders, are believed to arise later in tumor progression than the translocation event and contribute to ligand-independent signaling (Chesi, 1997; Chesi, 2001; Li, 2001; Ronchetti, 2001).
Overexpression of WT FGFR3 is weakly transforming when expressed in a mouse haematopoietic model, while expression of translocated FGFR3 carrying activating point mutations in the coding sequence is strongly transforming in both NIH 3T3 cells and the haematopoietic mouse model (Chesi, 2001; Ronchetti, 2001; Li, 2001). Activating mutations in FGFR3 are mutually exclusive with activating Ras mutations, and focus formation in NIH 3T3 cells is inhibited by cotransfection with dominant negative forms of ras or raf, suggesting that activation of the MAPK pathway is the primary oncogenic event in translocated myeloma lines (Chesi, 2001). Inhibition of FGFR3 in multiple myeloma lines and tumors has been shown to inhibit proliferation (Grand, 2004; Qing, 2009; Trudel, 2009; Krejci, 2010)
FGFR3 has been shown to be a target of a range of different tyrosine kinase inhibitors, including those restricted to in vitro use as well as a number that are currently in clinical trials for therapeutic use (see for instance, Paterson, 2004; Trudel, 2004; Trudel, 2005; Grand, 2004, Chen, 2005; Bernard-Pierrot, 2006; http::/clinicaltrials.gov). There are also two anti-FGFR3 antibodies that have shown preliminary promise in cancer cell lines or mouse models (Qing, 2009; Trudel, 2006).
Dissociation from the activated receptor quickly follows phosphorylation of PLC-gamma. Phosphorylated PLC-gamma catalyzes the hydrolysis of phosphatidylinositol(4, 5)bisphosphate to generate two second messengers, diacylglycerol and inositol (1,4,5) triphosphate.
PLC gamma is phosphorylated by activated FGFR, resulting in PLC gamma activation, stimulation of phosphatidyl inositol hydrolysis and generation of two second messengers, diacylglycerol and inositol (1,4,5) P3. Tyrosine phosphorylation of PLCgamma by FGFR4 is weaker than that seen by other isoforms of FGFR.
Recruitment of PLC-gamma by FGF receptors has been best studied in FGFR1c signaling, where it has been shown that autophosphorylation of Tyr766 in the C-terminal tail of FGFR1c creates a specific binding site for the SH2 domain of PLC-gamma. A mutant FGFR1c in which Y766 is replaced by phenylalanine is unable to activate PI hydrolysis and Ca2+ release in response to FGF stimulation. Membrane recruitment of PLC-gamma is also aided by binding of the Pleckstrin homology (PH) domain of this enzyme to PtIns(3,4,5) P3 molecules that are generated in response to PI-3 kinase stimulation. By sequence comparison, Y766 is conserved in all FGFR isoforms, and PLC-gamma signaling is observed, to a greater or lesser extent, downstream of all FGFR receptors upon stimulation with FGFs.
FRS2 (also known as FRS alpha is activated through tyrosine phosphorylation catalyzed by the protein kinase domain of the activated FGFR. FRS2 contains four binding sites for the adaptor protein GRB2 at residues Y196, Y306, Y349 and Y392, and two binding sites for the protein tyrosine phosphatase PPTN11/SHP2 at residues Y436 and Y471. Different FGFR isoforms may generate different phosphorylation patterns on FRS2 leading to alternate downstream signaling.
FRS2 (also known as FRS2alpha) is broadly expressed in adult and fetal tissues. Membrane-bound FRS2 interacts with FGFR as a first step in the phosphorylation of this docking protein. The juxtamembrane binding site for FRS2 does not contain tyrosine, so binding may be independent of receptor activation and/or constitutive. Activation of the FGFR receptor is required for FRS2 phosphorylation and subsequent recruitment of downstream effectors.
Tyrosine phosphorylated FRS2 recruits GRB2:SOS1 complex by means of the SH3 domain of GRB2, leading to RAS-MAP kinase activation. The FRS2:GRB2-mediated pathway plays a minor role in the activation of RAS-MAP kinase pathway compared to that mediated by FRS2:PPTN11.
FRS2 has 8 canonical MAPK phosphorylation sites which are phosphorylated by activated ERK1/2 after FGF stimulation. Phosphorylation of these 8 threonine residues counteracts the activating effect of tyrosine phosphorylation of FRS2, although the exact mechanism for this negative regulation is not known. Expression of a version of FRS2 in which the 8 threonine residues are mutated to valine results in enhanced tyrosine phosphorylation of FRS2, enhanced GRB2-SOS1 recruitment and a more sustained MAPK response. The 8 threonine residues are not conserved in FRS3; as a result, signaling through FRS3 complexes do not appear to be subject to this downregulation.
FRS3 (also known as FRS2beta) is predominantly expressed in the developing and adult neuroepithelium. As is the case for FRS2 (also known as FRS2alpha), binding of FRS3 to FGFR may be constitutive and/or independent of receptor activation. Elements of the downstream signaling mediated by the two FRS family members appear to be at least partially conserved, as FRS3 is phosphorylated upon FGF stimulation, binds PPTN11/SHP2 and GRB2 and results in ERK activation. Moreover, expression of FRS3 in FRS2-/- MEFs restores ERK activation.
FRS3 (also known as FRS2 beta) is activated through tyrosine phosphorylation catalyzed by the protein kinase domain of the activated FGFR. By sequence comparison, FRS3 has the 2 PPTN11/SHP2-binding sites and has three of the four GRB2-binding sites.
Tyrosine phosphorylation of PPTN11/SHP2 by FGFR kinase is required for activation of the phosphatase activity of PPTN11 and for downstream signaling. Tyrosine phosphorylated PPTN11 plays a major role in the activation of RAS-MAP kinase pathway, although the precise role is not yet clear.
The p46 and p53 isoforms of SHC1 have been shown to be phosphorylated upon FGF stimulation. Three consensus RTK phosphoryation sites are present in SHC1, although phosphorylation of these specific tyrosine residues has not been explicitly demonstrated in response to FGF stimulation. In contrast, the p66 isoform of SHC1 does not appear to undergo FGF-dependent phosphorylation.
Phosphorylated SHC1 links FGFR to Grb2 (Klint et al. 1995) leading to the formation of a signaling complex including Shc, Grb2 and Sos. Transformation of NIH 3T3 cells with v-Src produced a strong constitutive association of FGFR1 with Shc, Grb2 and Sos (Curto et al. 1998) suggesting Src involvement. Recruitment of Grb2-Sos links FGFR to the Ras pathway.
Grb2 bound to tyrosine phosphorylated FRS2 forms a ternary complex with Cbl through the binding of the SH3 domains of Grb2 to a proline rich region in Cbl. Grb2-mediated recruitment of Cbl results in ubiquitination of FGFR and FRS2. Cbl is a multidomain protein that posses an intrinsic ubiquitin ligase activity and also functions as a platform for recruitment of a variety of signaling proteins. Multiple mechanisms appear to be required for downregulation of FGFR, as internalization of the receptor is reduced but not abolished if recruitment of CBL to FRS2 is compromised by mutation of GRB2-binding sites.
Once recruited to the activated receptor, PI3K phosphorylates PIP2 to PIP3, leading to activation of AKT signaling. PI3K signaling has been demonstrated in ZMYM2-, FOP- and BCR-FGFR1 fusions (Chen, 2004; Demiroglu, 2001; Guasch, 2001), as well as downstream of a number of other FGFR mutants (see for instance, Byron, 2008; Kunii, 2008; Agazie, 2003; Takeda, 2007).
The ubiquitin ligase CBL exists in a complex with GRB2 and is recruited to tyrosine-phosphorylated FRS2 after FGF stimulation. In addition to promoting the ubiquitination, endocytosis, and degradation of the activated receptor complex, recruitment of the p-CBL:GRB2 complex seems to attenuate FGFR signaling by competing with GRB2:SOS1 for binding to the direct GRB2-binding sites on p-FRS2.
Fibroblast growth factor 23 (FGF23, aka phosphatonin) is a regulator of phosphate homeostasis and vitamin D metabolism. Its effects are thought to be mediated via the FGFR3c receptor. Glycosylation is necessary for FGF23 secretion from the cell and that is mediated by polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), which transfers an N-acetylgalactosaminyl (GalNAc) moiety from a high energy donor to threonine 178 on FGF23 (Kato et al. 2006). Competition between proprotein convertase cleavage and O-glycosylation determines the level of secreted active FGF23.
FGFR3 fusions promote cellular proliferation and tumorigenesis that can be inhibited by tyrosine kinase inhibitors, suggesting that signaling is dependent on autophosphorylation of tyrosine residues in the intracellular region as is the case for WT FGFR3 (Singh et al, 2012; Parker et al, 2013; Williams et al, 2013; Wu et al, 2013; Yuan et al, 2014). FGFR3 fusions are reported to activate the ERK , STAT and AKT pathways, but not the PLC gamma pathway as the fusions generally lack the tyrosine residue required for PLC gamma recruitment (Parker et al, 2013; Williams et al, 2013; Wu et al, 2013; reviewed in Parker et al, 2014; Carter et al, 2015).
Constitutively active fusions of FGFR3 have been identified in glioblastoma, non-small cell lung cancer and bladder cancer, among others (Singh et al, 2012; Williams et al, 2013; Wu et al, 2013; Wang et al, 2014; Capelletti et al, 2014; Yuan et al, 2015; Carneiro et al, 2015; reviewed in Parker et al, 2014). The most prevalent fusion partner is TACC3 (transforming acidic coiled-coil-containing protein 3), a microtubule binding protein with roles in microtubule spindle assembly and chromosome segregation (Singh et al, 2014; Burgess et al, 2015; reviewed in Parker et al, 2014). There are conflicting reports about whether FGFR3 fusions form constitutive dimers, however ligand-independent autophosphorylation and downstream signaling has been demonstrated. FGFR3 fusions promote cellular proliferation and tumorigenesis and appear to escaped miRNA-mediated downregulation (Singh et al, 2012; Williams et al, 2013; Wu et al, 2013; Parker et al, 2013; reviewed in Parker et al, 2014).
RAS nucleotide is stimulated downstream of activated FGFR3 in a p-PTPN11-dependent manner. The phosphatase activity of PTPN11 is required for activation of the RAS-MAP kinase pathway, although the mechanism for RAS pathway activation is not yet clear (Hadari et al, 1998; reviewed in Mohi et al, 2007; Gotoh et al, 2008).
In humans, the phosphorylated MNK1 kinase phosphorylates the adaptor protein Sprouty2 on Ser112 and Ser121, and also at some other serine and threonine residues. MNK1 appears not to form a complex with Sprouty2. Some of these (including the two main sites mentioned above) conform to the serine-containing consensus sites for phosphorylation by MNK1 kinase (K/R-X-X-S, R-X-S). It appears that serine phosphorylation is required to protect Sprouty2 from degradation.
In the absence of serine phosphorylation, phosphorylation of Tyr55 and subsequent binding to E3 ubiquitin ligase, CBL, is enhanced. Serine phosphorylation of Sprouty2 appears to stabilise the protein by interfering with its potential phosphorylation of Tyr55 (Sprouty2 appears to be a poor substrate for c-Src kinase) in response to growth factor stimulation.
In humans, the phosphorylated adaptor protein Sprouty2 is ubiquitinated by the E3 ubiquitin ligase CBL, marking it for degradation by the 26S proteasome.
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
mutants with enhanced kinase
activityt(4;14) translocation
mutantstranslocation
mutant dimerstranslocation
mutantsdimers with enhanced kinase
activitywith enhanced
kinase activity(A:C):S112/S115
p-SPRY2The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
inhibitors of FGFR3
mutantsAnnotated Interactions
mutants with enhanced kinase
activityt(4;14) translocation
mutantstranslocation
mutant dimerstranslocation
mutant dimerstranslocation
mutant dimerstranslocation
mutantsdimers with enhanced kinase
activitydimers with enhanced kinase
activitydimers with enhanced kinase
activitywith enhanced
kinase activity(A:C):S112/S115
p-SPRY2(A:C):S112/S115
p-SPRY2SPRY2 has also been shown to be phosphorylated at multiple tyrosine residues in its C-terminal in response to FGF, but not EGF, stimulation. This phosphorylation, in particular at residue 227, is thought to augment the ability of SPRY2 to inhibit FGF signaling through the MAPK cascade, although the mechanism remains to be elucidated.
In the absence of serine phosphorylation, phosphorylation of Tyr55 and subsequent binding to E3 ubiquitin ligase, CBL, is enhanced. Serine phosphorylation of Sprouty2 appears to stabilise the protein by interfering with its potential phosphorylation of Tyr55 (Sprouty2 appears to be a poor substrate for c-Src kinase) in response to growth factor stimulation.
inhibitors of FGFR3
mutants