Autocatalytic phosphorylation of FGFR2 point mutants with enhanced kinase activity

Stable Identifier
Reaction [transition]
Homo sapiens
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Several missense mutations in the tyrosine kinase domain of FGFR2 have been identified in Crouzon syndrome and similar craniosynostosis disorders (Kan, 2002; Cunningham, 2007). The N549H and K660N mutations identified in FGFR2 in craniosynostosis disorders are paralogous to FGFR3 N540K and K650N/E mutations identified in hypochondroplasia and thanatophoric dysplasia II (Bellus, 2000). In FGFR3, these mutations have been demonstrated to have weak ligand-independent autophosphorylation and enhanced kinase activity mediated by disruption of a hydrogen-bonding network that holds the receptor in an inactive conformation (Chen, 2007; Bellus, 2000, Raffioni, 1998).

Characterization of FGFR2 proteins containing somatic mutations at these residues support the notion that they have elevated levels of kinase activity. FRS2 is constitutively phosphorylated in the FGFR2 N549K kinase mutant identified in endometrial tumors and knockdown of N549K with short hairpin RNAs or the pan-FGFR inhibitor PD170734 inhibits cell survival in endometrial cancer cells lines, suggesting that FGFR2 activity is required for tumor cell survival. FGFR2 knockdown also results in a significant decrease in the levels of phosphorylated Erk1/2 (Dutt, 2008; Byron, 2008; Pollock, 2007). Crystal structures of FGFR2 kinase mutants N549H and K650N show that the mutations disengage an 'auto-inhibitory brake' on the kinase domain of the receptor. Biochemically, the FGFR2 N549K and K660E mutants show elevated kinase activity relative to the unphosphorylated wild-type protein and have increased activity towards peptide substrates; this activity is stimulated upon receptor phosphorylation, but to a lesser extent than seen with the wild-type receptor (Chen, 2007).
Literature References
PubMed ID Title Journal Year
18757403 Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation

Pollock, PM, Wellens, CL, Goodfellow, PJ, Gartside, MG, Mallon, MA, Powell, MA, Byron, SA, Keenan, JB

Cancer Res 2008
9857065 Effect of transmembrane and kinase domain mutations on fibroblast growth factor receptor 3 chimera signaling in PC12 cells. A model for the control of receptor tyrosine kinase activation

Thompson, LM, Raffioni, S, Bradshaw, RA, Zhu, YZ

J Biol Chem 1998
17525745 Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes

Futreal, PA, Pollock, PM, Goodfellow, PJ, Gartside, MG, Stratton, MR, Davies, H, Mallon, MA, Mohammadi, M, Dejeza, LC, Powell, MA, Trent, JM

Oncogene 2007
17552943 Syndromic craniosynostosis: from history to hydrogen bonds

Cunningham, ML, Heike, CL, Seto, ML, Hing, AV, Ratisoontorn, C

Orthod Craniofac Res 2007
17803937 A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases

Eliseenkova, AV, Miller, WT, Chen, H, Li, W, Mohammadi, M, Xu, C, Ma, J, Neubert, TA

Mol Cell 2007
18552176 Drug-sensitive FGFR2 mutations in endometrial carcinoma

Akslen, LA, Cibulskis, K, Greulich, H, Dutt, A, Sellers, WR, Chen, TH, Winckler, W, Wyhs, N, Ziaugra, L, Zody, MC, Salvesen, HB, Meyerson, M, Stefansson, IM, Trovik, J, Wong, KK, Ramos, AH, Richter, DJ, Gabriel, S, Nicoletti, R, Onofrio, RC, Grewal, R, Hanna, M, Hatton, C, Engelsen, IB, Fennell, T

Proc Natl Acad Sci U S A 2008
11781872 Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis

Elanko, N, Rannan-Eliya, S, Muenke, M, Tomkins, S, Reich, EW, Twigg, SR, Zackai, EH, Verloes, A, McDonald-McGinn, DM, Wall, SA, Johnson, D, Cook, J, Kan, SH, Wilkie, AO, Cornejo-Roldan, L

Am J Hum Genet 2002
11055896 Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype

Francomano, CA, Spector, EB, Bellus, GA, Garber, AT, Israel, J, Bryke, CR, Speiser, PW, Donoghue, DJ, Weaver, CA, Webster, MK, Rosengren, SS

Am J Hum Genet 2000
Catalyst Activity

protein tyrosine kinase activity of FGFR2 mutant dimers with enhanced kinase activity [plasma membrane]

Functional status

Gain of function of FGFR2 mutant dimers with enhanced kinase activity [plasma membrane]

Disease Entity
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
bone development disease DOID:0080006
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