10817

FRS3

FRS2-beta|FRS2B|FRS2beta|SNT-2|SNT2;fibroblast growth factor receptor substrate 3;FRS3;fibroblast growth factor receptor substrate 3

FGFR substrate 3|FGFR-signaling adaptor SNT2|suc1-associated neurotrophic factor target 2 (FGFR signalling adaptor)

6p21.1

protein-coding

An adaptor protein FRS2beta inhibits epidermal growth factor-receptor (EGFR) tyrosine kinase without being phosphorylated at tyrosine residues after EGF stimulation. Although binding to ERK appears to be important for this inhibition, the precise molecular mechanisms and the role of FRS2beta in signal transduction mediated by other EGFR family members, as well as its role in human cancer, remain unclear. In this study, we demonstrate that FRS2beta inhibits anchorage-independent cell growth induced by oncogenic ErbB2, another member of EGFR family, and that it inhibits heterodimer formation between EGFR and ErbB2. We mapped the residues important for the FRS2beta and ERK interaction to two docking (D) domain-like sequences on FRS2beta and two aspartic acid residues in the common docking (CD) domain of ERK. Moreover, in response to EGF, ERK translocated to the plasma membrane in cells expressing FRS2beta but not an FRS2beta mutant in which four arginine residues in the D domains were replaced with alanines, suggesting that FRS2beta serves as a plasma membrane anchor for activated ERK. Finally, a low mRNA expression level of FRS2beta was significantly correlated with poor prognosis in a cohort of 60 non-small cell lung cancer patients. Therefore, we have identified the molecular mechanisms by which FRS2beta acts as a feedback inhibitor of EGFR family members and suggest a role for FRS2beta as a tumor suppressor.