PathwayStep4161 PathwayStep4160 PathwayStep4163 PathwayStep4162 PathwayStep4165 PathwayStep4164 PathwayStep4167 PathwayStep4166 PathwayStep4169 PathwayStep4168 PathwayStep4172 PathwayStep4171 PathwayStep4170 PathwayStep4176 PathwayStep4175 PathwayStep4174 PathwayStep4173 p-BCR-pFGFR1 recruits GRB2:GAB2 GAB2 is phosphorylated by p-BCR-p-FGFR1 FGFR1 fusion protein-associated PI3K phosphorylates PIP2 to PIP3 Phosphorylation of BCR moiety of BCR-FGFR1 Recruitment of the catalytic subunit of PI3K to activated FGFR1 fusions FGFR1OP-FGFR1 phosphorylates STAT1 and STAT3 Phosphorylation of STAT5 by FGFR1 fusions BCR-FGFR1-associated PI3K phosphorylates PIP2 to PIP3. The catalytic subunit of PI3K is recruited to the BCR-FGFR1 fusion. Recruitment of the p85 regulatory subunit of PI3K to the BCR-FGFR1 complex. Dimerization of FGFR1 fusion proteins p-PLCgamma dissociates from FGFR1 fusions FGFR1 fusion proteins recruit PIK3R1 FGFR1 fusions bind PLCgamma PLCgamma is phosphorylated by FGFR1-fusions Phosphorylation of FGFR1 fusion dimers Tyrosine kinase inhibitors bind and inhibit FGFR1 fusion dimer phosphorylation Signaling by FGFR1 fusion mutants 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). <br><br>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). <br>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(Lelièvre, 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). Authored: Rothfels, K, 2012-02-09 Edited: Rothfels, K, 2012-05-16 Pubmed10480903 Pubmed10935490 Pubmed11689702 Pubmed11739186 Pubmed15050920 Pubmed17698633 Pubmed18412956 Pubmed20094046 Pubmed20226962 Pubmed21330321 Pubmed21367659 Pubmed21711248 Reactome Database ID Release 431839117 Reactome, http://www.reactome.org ReactomeREACT_121141 Reviewed: Ezzat, S, 2012-05-15