The membrane-linked docking protein FRS2beta becomes tyrosine phosphorylated in response to fibroblast growth factors (FGFs) and neurotrophins and serves as a platform for recruitment of multiple signaling proteins, including Grb2 and Shp2, to FGF receptors or neurotrophin receptors. We previously reported that FRS2beta is not tyrosine phosphorylated significantly in response to epidermal growth factor (EGF) but that it inhibits ERK activation via EGF stimulation by forming a complex with ERK2. In the present report, we show that expression of FRS2beta suppressed EGF-induced cell transformation and proliferation, and expression level of FRS2beta is down-regulated in cancer. The activities of the major signaling molecules in EGF receptor (EGFR) signal transduction pathways, including autophosphorylation of EGFR, were attenuated in cells expressing FRS2beta but not in cells expressing FRS2beta mutants lacking the ERK2-binding domain. Furthermore, FRS2beta constitutively bound to EGFR through the phosphotyrosine binding (PTB) domain both with and without EGF stimulation. Treatment of cells with MEK inhibitor U0126 partially restored the phosphorylation levels of MEK and EGFR in cells expressing FRS2beta. On the basis of these findings, we propose a novel mechanism of negative control of EGFR tyrosine kinase activity with FRS2beta by recruiting ERK2, which is the site of negative-feedback loop from ERK, ultimately leading to inhibition of EGF-induced cell transformation and proliferation.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA