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

Warning

This publication doesn't include Faculty of Medicine. It includes Faculty of Science. Official publication website can be found on muni.cz.

Authors

SALAZAR Lisa KASHIWADA Tamara KREJČÍ Pavel MUCHOWSKI Paul DONOGHUE Daniel WILCOX William THOMPSON Leslie Michels

Year of publication 2008
Type Article in Periodical
Magazine / Source HUMAN MOLECULAR GENETICS
MU Faculty or unit

Faculty of Science

Citation
Field Genetics and molecular biology
Keywords GAMMA-INDEPENDENT PATHWAYS; PHOSPHATIDYLINOSITOL 3-KINASE; SIGNALING PATHWAY; FGFR3 MUTANTS; HEMATOPOIETIC TRANSFORMATION; THERAPEUTIC TARGET; TUMOR PROGRESSION; DOCKING PROTEIN; CANCER CELLS; PC12 CELLS
Description 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 alpha, as a novel interactor of FGFR3 by yeast two-hybrid, and confirmed an interaction with both p85 alpha and p85 beta 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 gamma binding site. The interaction of p85 with FGFR3 does not require PLC gamma, suggesting the p85 interaction is direct and independent of PLC gamma binding. FGFR3 and p85 proteins also interact in MM cell lines which consistently express p85 alpha and p85 beta, but not p50 or p55 subunits. siRNA knockdown of p85 beta 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.
Related projects:

You are running an old browser version. We recommend updating your browser to its latest version.

More info