Autocatalytic phosphorylation of FGFR1 mutants with enhanced kinase activity

Stable Identifier
R-HSA-2023460
Type
Reaction [transition]
Species
Homo sapiens
Compartment
plasma membrane, cytosol
ReviewStatus
5/5
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Autocatalytic phosphorylation of FGFR1 mutants with enhanced kinase activity
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The three kinase domain mutants of FGFR1 that have been identified in glioblastoma are predicted or have been shown to result in enhanced kinase activity. The N546K (Rand, 2005) residue lies in a stretch of 9 amino acids that are conserved between all four FGFRs. Mutation of the paralogous residue in FGFR3 (N540K) has been shown to result in weak ligand-independent contstitutive activation in the autosomal disorder hypochodroplasia (Raffioni, 1998). In FGFR2 mutation of the paralogous residue to lysine has been identified in endometrial cancer and been shown to result in enhanced kinase activity (Dutt, 2008; Pollock, 2008); germline mutations at this site in FGFR2 are also associated with the development of Crouzon and Pfeiffer syndromes (Kan, 2002). The FGFR1 N546K mutations has accelerated rates of autophosphorylation and supports transformation when transfected into Rat-1 cells (Lew, 2009).


The FGFR1 K656E (TCGA, 2008) mutation is paralogous to activating mutations in FGFR3 kinase domain associated with the development of thanatophoric dysplasias (Tavormina, 1999; Bellus, 2000; Hart, 2000), and has itself been shown to activating when expressed in neural crest cells (Petiot, 2002).


The FGFR1 R576W (Rand, 2005) mutation increases the hydrophobicity of the receptor, and is postulated to enhance protein-protein interactions and thereby increase the likelihood of autophosphorylation of adjacent tyrosine residues, although this has not been explicitly demonstrated.


Literature References
PubMed ID Title Journal Year
18772890 Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Cancer Genome Atlas Research Network, -

Nature 2008
19224897 The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations

Lew, ED, Furdui, CM, Anderson, KS, Schlessinger, J

Sci Signal 2009
10053006 A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene

Tavormina, PL, Bellus, GA, Webster, MK, Bamshad, MJ, Fraley, AE, McIntosh, I, Szabo, J, Jiang, W, Jabs, EW, Wilcox, WR, Wasmuth, JJ, Donoghue, DJ, Thompson, LM, Francomano, CA

Am J Hum Genet 1999
17525745 Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes

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

Oncogene 2007
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

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

J Biol Chem 1998
10918587 Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4

Hart, KC, Robertson, SC, Kanemitsu, MY, Meyer, AN, Tynan, JA, Donoghue, DJ

Oncogene 2000
16186508 Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas

Rand, V, Huang, J, Stockwell, T, Ferriera, S, Buzko, O, Levy, S, Busam, D, Li, K, Edwards, JB, Eberhart, C, Murphy, KM, Tsiamouri, A, Beeson, K, Simpson, AJ, Venter, JC, Riggins, GJ, Strausberg, RL

Proc Natl Acad Sci U S A 2005
12112473 Induction of chondrogenesis in neural crest cells by mutant fibroblast growth factor receptors

Petiot, A, Ferretti, P, Copp, AJ, Chan, CT

Dev Dyn 2002
18552176 Drug-sensitive FGFR2 mutations in endometrial carcinoma

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

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

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

Am J Hum Genet 2002
Participants
Input
Output
Participates
as an event of
Catalyst Activity

protein tyrosine kinase activity of FGFR1 mutant dimers with enhanced kinase activity [plasma membrane]

Physical Entity
FGFR1 mutant dimers with enhanced kinase activity [plasma membrane] (Homo sapiens)
Activity
protein tyrosine kinase activity (GO:0004713)
Functional status

Gain of function of FGFR1 mutant dimers with enhanced kinase activity [plasma membrane]

Disease Entity
Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
glioblastoma DOID:3068 GBM, adult glioblastoma multiforme, grade IV adult Astrocytic tumor, primary glioblastoma multiforme, spongioblastoma multiforme
Cross References
Mondo
Authored
Rothfels, K  (2012-02-10)
Reviewed
Ezzat, S  (2012-05-15)
Created
Rothfels, K  (2011-12-08)
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