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Signaling by FGFR1 in disease

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-5655302

PubChem

R-HSA-5655302

Description

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).

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying entries **1 - 10** of 19 in total

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UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
O15164	Transcription intermediary factor 1-alpha	RNF82 TIF1 TIF1A TRIM24	view
O94905	Erlin-2	C8orf2 ERLIN2 SPFH2 UNQ2441/PRO5003/PRO9924	view
O95429	BAG family molecular chaperone regulator 4	BAG4 SODD	view
O95684	Centrosomal protein 43	CEP43 FGFR1OP FOP	view
P01111	GTPase NRas	HRAS1 NRAS	view
P01112	GTPase HRas	HRAS HRAS1	view
P10767	Fibroblast growth factor 6	FGF6 HST2 HSTF2	view
P11274	Breakpoint cluster region protein	BCR BCR1 D22S11	view
P11362	Fibroblast growth factor receptor 1	BFGFR CEK FGFBR FGFR1 FLG FLT2 HBGFR hCG_23105	view
P19174	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1	PLC1 PLCG1	view

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