Details

Autor(en) / Beteiligte

• Iejima, D
• Minegishi, Y
• Takenaka, K
• Siswanto, A
• Watanabe, M
• Huang, L
• Watanabe, T
• Tanaka, F
• Kuroda, M
• Gotoh, N

Titel

FRS2β, a potential prognostic gene for non-small cell lung cancer, encodes a feedback inhibitor of EGF receptor family members by ERK binding

Ist Teil von

• Oncogene, 2010-05, Vol.29 (21), p.3087-3099

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2010

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• An adaptor protein FRS2β 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 FRS2β 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 FRS2β 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 FRS2β and ERK interaction to two docking (D) domain-like sequences on FRS2β 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 FRS2β but not an FRS2β mutant in which four arginine residues in the D domains were replaced with alanines, suggesting that FRS2β serves as a plasma membrane anchor for activated ERK. Finally, a low mRNA expression level of FRS2β 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 FRS2β acts as a feedback inhibitor of EGFR family members and suggest a role for FRS2β as a tumor suppressor.