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Signaling by cytosolic FGFR1 fusion mutants

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-1839117

PubChem

R-HSA-1839117

Description

8p11 myeloproliferative syndrome (EMS) is an aggressive disorder that is associated with a translocation event at the FGFR1 gene on chromosome 8p11. Typical symptoms upon diagnosis include eosinophilia and associated T-cell lymphoblastic lymphoma; the disease rapidly advances to acute leukemia, usually of myeloid lineage. At present the only effective treatment is allogenic stem cell transplantation (reviewed in Jackson, 2010).

At the molecular level, EMS appears to be caused by translocation events on chromosome 8 that create gene fusions between the intracellular domain of FGFR1 and an N-terminal partner gene that encodes a dimerization domain. The resulting fusion protein dimerizes in a ligand-independent fashion based the N-terminal domain provided by the partner protein and stimulates constititutive downstream FGFR1 signaling without altering the intrisic kinase activity of the receptor. To date, 11 partner genes have been identified: ZMYM2, FGFR1OP, FGFR1OP2, HERVK, TRIM24, CUX1, BCR, CEP110, LRRFIP1, MYO18A and CPSF6, although not all have been functionally characterized (reviewed in Jackson, 2010, Turner and Grose, 2010; Wesche, 2011).
Where examined, cell lines carrying FGFR1 fusion genes have been shown to be transforming and to support IL3-independent proliferation through anti-apoptotic, prosurvival pathways(Lelievre, 2008; Ollendorff, 1999; Chase, 2007; Guasch, 2001; Wasag 2011; Roumiantsev, 2004; Demiroglu, 2001; Smedley, 1999). Signaling appears to occur predominantly through PLCgamma, PI3K and STAT signaling, with a more minor contribution from MAPK activation. Because the fusion proteins lack the FRS2-binding site, the mechanism of MAPK activation is unclear. Recruitment of GRB2:SOS1 through recruitment of SHC is one possibility (Guasch, 2001).

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 11 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
O95684	Centrosomal protein 43	CEP43 FGFR1OP FOP	view
P11274	Breakpoint cluster region protein	BCR BCR1 D22S11	view
P39880	Homeobox protein cut-like 1	CUTL1 CUX1	view
P40763	Signal transducer and activator of transcription 3	APRF STAT3	view
P42224	Signal transducer and activator of transcription 1-alpha/beta	STAT1	view
P42229	Signal transducer and activator of transcription 5A	STAT5 STAT5A	view
P51692	Signal transducer and activator of transcription 5B	STAT5B	view
Q16630	Cleavage and polyadenylation specificity factor subunit 6	CFIM68 CPSF6	view
Q32MZ4	Leucine-rich repeat flightless-interacting protein 1	GCF2 LRRFIP1 TRIP	view

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