Adaptor protein complex of FRS2 beta and CIN85/CD2AP provides a novel mechanism for ErbB2/HER2 protein downregulation

作者:Minegishi Yuriko; Shibagaki Yoshio; Mizutani Anna; Fujita Koji; Tezuka Tohru; Kinoshita Masao; Kuroda Masahiko; Hattori Seisuke; Gotoh Noriko*
来源:Cancer Science, 2013, 104(3): 345-352.
DOI:10.1111/cas.12086

摘要

Overexpression of the ErbB2/HER2 receptor tyrosine kinase contributes to tumorigenesis. However, mechanisms regulating ErbB2 protein levels remain largely unclear. Here, we identified novel mechanisms of ErbB2 downregulation. ErbB2 constitutively binds to an adaptor protein FRS2. We found that FRS2 bound to CD2AP and CIN85, which induces endosomal trafficking that targets lysosomes. FRS2 colocalized with CIN85 in the cytoplasm. Expression of wild type FRS2 but not its CIN85 non-binding mutant, downregulated the ErbB2 protein and inhibited anchorage-independent cell growth. Moreover, the E3 ubiquitin-protein ligase Cbl was contained within a complex of FRS2 and CIN85. Knockdown of both CIN85 and CD2AP or of Cbl, or treatment with lysosomal degradation inhibitors diminished FRS2 downregulation of ErbB2. In addition, knockdown of endogenous FRS2 caused upregulation of ErbB2 in primary neural cells. Finally, immunohistochemical analysis showed that human breast cancer tissues that overexpress ErbB2 expressed low levels of FRS2. Thus, an FRS2-CIN85/CD2AP-Cbl axis for downregulation of ErbB2 may regulate ErbB2 protein levels in physiological and pathological settings. Molecular targeting drugs that can increase or stabilize the ErbB2-FRS2-CIN85/CD2AP-Cbl axis may have promise for the control of ErbB2-overexpressing tumors.