Human Molecular Genetics Advance Access originally published online on March 13, 2009
Human Molecular Genetics 2009 18(11):1951-1961; doi:10.1093/hmg/ddp116
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A novel interaction between fibroblast growth factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase: activation-dependent regulation of ERK by p85 in multiple myeloma cells
1 Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-4260, USA 2 Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 3 Institute of Experimental Biology, Masaryk University, 61265 Brno, Czech Republic 4 Department of Cytokinetics, Institute of Biophysics ASCR, 61265 Brno, Czech Republic 5 Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA 6 Department of Biochemistry and Biophysics 7 Department of Neurology, University of California, San Francisco, CA 94158, USA 8 Department of Chemistry and Biochemistry, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093-0367, USA 9 Department of Pediatrics, UCLA School of Medicine, Los Angeles, CA 90048, USA 10 Department of Neurobiology and Behavior 11 Department of Biological Chemistry, University of California, Irvine, CA 92697-4260, USA
* To whom correspondence should be addressed at: Department of Psychiatry and Human Behavior, University of California, Gillespie 2121, Irvine, CA 92697-4260, USA. Tel: +1 9498246756; Fax: +1 9498242577; Email: lmthomps{at}uci.edu
Received January 19, 2009; Accepted March 9, 2009
Ectopic activation of fibroblast growth factor receptor 3 (FGFR3) is associated with several cancers, including multiple myeloma (MM). FGFR3 inhibition in these cells inhibits proliferation and induces apoptosis, validating FGFR3 signaling as a therapeutic target in t(4;14) MM cases. We have identified the PI3K regulatory subunit, p85
, as a novel interactor of FGFR3 by yeast two-hybrid, and confirmed an interaction with both p85 and p85β in mammalian cells. The interaction of FGFR3 with p85 is dependent upon receptor activation. In contrast to the Gab1-mediated association of FGFRs with p85, the FGFR3-p85 interaction we observed requires FGFR3 Y760, previously identified as a PLC
binding site. The interaction of p85 with FGFR3 does not require PLC, suggesting the p85 interaction is direct and independent of PLC binding. FGFR3 and p85 proteins also interact in MM cell lines which consistently express p85 and p85β, but not p50 or p55 subunits. siRNA knockdown of p85β in MM cells caused an increased ERK response to FGF2. These data suggest that an endogenous negative regulatory role for the p85-FGFR3 interaction on the Ras/ERK/MAPK pathway may exist in response to FGFR3 activity and identifies a novel therapeutic target for MM.