Signaling by FGFR1 in disease

Stable Identifier
R-HSA-5655302
Type
Pathway
Species
Homo sapiens
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The FGFR1 gene has been shown to be subject to activating mutations, chromosomal rearrangements and gene amplification leading to a variety of proliferative and developmental disorders depending on whether these events occur in the germline or arise somatically (reviewed in Webster and Donoghue, 1997; Burke, 1998; Cunningham, 2007; Wesche, 2011; Greulich and Pollock, 2011).


Activating mutation P252R in FGFR1 is associated with the development of Pfeiffer syndrome, characterized by craniosynostosis (premature fusion of several sutures in the skull) and broadened thumbs and toes (Muenke, 1994; reviewed in Cunningham, 2007). This residue falls in a highly conserved Pro-Ser dipeptide between the second and third Ig domains of the extracellular region of the receptor. The mutation is thought to increase the number of hydrogen bonds formed with the ligand and to thereby increase ligand-binding affinity (Ibrahimi, 2004a). Unlike other FGF receptors, few activating point mutations in the FGFR1 coding sequence have been identified in cancer. Point mutations in the Ig II-III linker analagous to the P252R Pfeiffer syndrome mutation have been identified in lung cancer and melanoma (Ruhe, 2007; Davies, 2005), and two kinase-domain mutations in FGFR1 have been identified in glioblastoma (Rand, 2005, Network TCGA, 2008).

In contrast, FGFR1 is a target of chromosomal rearrangements in a number of cancers. FGFR1 has been shown to be recurrently translocated in the 8p11 myeloproliferative syndrome (EMS), a pre-leukemic condition also known as stem cell leukemia/lymphoma (SCLL) that rapidly progresses to leukemia. This translocation fuses the kinase domain of FGFR1 with the dimerization domain of one of 10 identified fusion partners, resulting in the constitutive dimerization and activation of the kinase (reviewed in Jackson, 2010).

Amplification of the FGFR1 gene has been implicated as a oncogenic factor in a range of cancers, including breast, ovarian, bladder, lung, oral squamous carcinomas, and rhabdomyosarcoma (reviewed in Turner and Grose, 2010; Wesche, 2011; Greulich and Pollock, 2011), although there are other candidate genes in the amplified region and the definitive role of FGFR1 has not been fully established.
More recently, FGFR1 fusion proteins have been identified in a number of cancers; these are thought to undergo constitutive ligand-independent dimerization and activation based on dimerization motifs found in the fusion partners (reviewed in Parker, 2014).

Literature References
PubMed ID Title Journal Year
21367659 Targeting mutant fibroblast growth factor receptors in cancer

Greulich, H, Pollock, PM

Trends Mol Med 2011
18772890 Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Cancer Genome Atlas Research, Network

Nature 2008
9154000 FGFR activation in skeletal disorders: too much of a good thing

Webster, MK, Donoghue, DJ

Trends Genet 1997
16140923 Somatic mutations of the protein kinase gene family in human lung cancer

Davies, H, Hunter, C, Smith, R, Stephens, P, Greenman, C, Bignell, G, Teague, J, Butler, A, Edkins, S, Stevens, C, Parker, A, O'Meara, S, Avis, T, Barthorpe, S, Brackenbury, L, Buck, G, Clements, J, Cole, J, Dicks, E, Edwards, K, Forbes, S, Gorton, M, Gray, K, Halliday, K, Harrison, R, Hills, K, Hinton, J, Jones, D, Kosmidou, V, Laman, R, Lugg, R, Menzies, A, Perry, J, Petty, R, Raine, K, Shepherd, R, Small, A, Solomon, H, Stephens, Y, Tofts, C, Varian, J, Webb, A, West, S, Widaa, S, Yates, A, Brasseur, F, Cooper, CS, Flanagan, AM, Green, A, Knowles, M, Leung, SY, Looijenga, LH, Malkowicz, B, Pierotti, MA, Teh, BT, Yuen, ST, Lakhani, SR, Easton, DF, Weber, BL, Goldstraw, P, Nicholson, AG, Wooster, R, Stratton, MR, Futreal, PA

Cancer Res 2005
9538690 Fibroblast growth factor receptors: lessons from the genes

Burke, D, Wilkes, D, Blundell, TL, Malcolm, S

Trends Biochem Sci 1998
21711248 Fibroblast growth factors and their receptors in cancer

Wesche, J, Haglund, K, Haugsten, EM

Biochem J 2011
24588013 Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours

Parker, BC, Engels, M, Annala, M, Zhang, W

J. Pathol. 2014
14613973 Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity

Ibrahimi, OA, Zhang, F, Eliseenkova, AV, Linhardt, RJ, Mohammadi, M

Hum Mol Genet 2004
7874169 A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome

Muenke, M, Schell, U, Hehr, A, Robin, NH, Losken, HW, Schinzel, A, Pulleyn, LJ, Rutland, P, Reardon, W, Malcolm, S

Nat Genet 1994
20094046 Fibroblast growth factor signalling: from development to cancer

Turner, N, Grose, RP

Nat Rev Cancer 2010
20226962 8p11 myeloproliferative syndrome: a review

Jackson, CC, Medeiros, LJ, Miranda, RN

Hum Pathol 2010
17552943 Syndromic craniosynostosis: from history to hydrogen bonds

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

Orthod Craniofac Res 2007
18056464 Genetic alterations in the tyrosine kinase transcriptome of human cancer cell lines

Ruhe, JE, Streit, S, Hart, S, Wong, CH, Specht, K, Knyazev, P, Knyazeva, T, Tay, LS, Loo, HL, Foo, P, Wong, W, Pok, S, Lim, SJ, Ong, H, Luo, M, Ho, HK, Peng, K, Lee, TC, Bezler, M, Mann, C, Gaertner, S, Hoefler, H, Iacobelli, S, Peter, S, Tay, A, Brenner, S, Venkatesh, B, Ullrich, A

Cancer Res 2007
Participants
Participant Of
Disease
Name Identifier Synonyms
bone development disease 0080006
cancer 162 malignant tumor, malignant neoplasm, primary cancer
Authored
Reviewed
Created