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.
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, p85alpha, as a novel interactor of FGFR3 by yeast two-hybrid, and confirmed an interaction with both p85alpha and p85beta 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 PLCgamma binding site. The interaction of p85 with FGFR3 does not require PLCgamma, suggesting the p85 interaction is direct and independent of PLCgamma binding. FGFR3 and p85 proteins also interact in MM cell lines which consistently express p85alpha and p85beta, but not p50 or p55 subunits. siRNA knockdown of p85beta 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.
Salazar
Lisa
L
1Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-4260, USA.
Kashiwada
Tamara
T
Krejci
Pavel
P
Muchowski
Paul
P
Donoghue
Daniel
D
Wilcox
William R
WR
Thompson
Leslie Michels
LM
D001665:Binding Sites; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009101:Multiple Myeloma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
D019869:Phosphatidylinositol 3-Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D048049:Extracellular Signal-Regulated MAP Kinases