title: Adaptor protein complex of FRS2β and CIN85/CD2AP provides a novel mechanism for ErbB2/HER2 protein downregulation.
abstract: 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 FRS2β. We found that FRS2β bound to CD2AP and CIN85, which induces endosomal trafficking that targets lysosomes. FRS2β colocalized with CIN85 in the cytoplasm. Expression of wild type FRS2β 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 FRS2β and CIN85. Knockdown of both CIN85 and CD2AP or of Cbl, or treatment with lysosomal degradation inhibitors diminished FRS2β downregulation of ErbB2. In addition, knockdown of endogenous FRS2β caused upregulation of ErbB2 in primary neural cells. Finally, immunohistochemical analysis showed that human breast cancer tissues that overexpress ErbB2 expressed low levels of FRS2β. Thus, an FRS2β-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-FRS2β-CIN85/CD2AP-Cbl axis may have promise for the control of ErbB2-overexpressing tumors.
authors.affiliation: Division of Systems Biomedical Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Minegishi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Shibagaki
authors.forename: Anna
authors.initials: A
authors.lastname: Mizutani
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.forename: Tohru
authors.initials: T
authors.lastname: Tezuka
authors.forename: Masao
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
authors.forename: Seisuke
authors.initials: S
authors.lastname: Hattori
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D001943:Breast Neoplasms / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D009474:Neurons / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D050721:Proto-Oncogene Proteins c-cbl; D018719:Erb-b2 Receptor Tyrosine Kinases; C113566:FRS3 protein, human; C514895:MVB12A protein, human; C433810:SH3KBP1 protein, human; C067419:CBL protein, human