title: Erbin loss promotes cancer cell proliferation through feedback activation of Akt-Skp2-p27 signaling.
abstract: Erbin localizes at the basolateral membrane to regulate cell junctions and polarity in epithelial cells. Dysregulation of Erbin has been implicated in tumorigenesis, and yet it is still unclear if and how disrupted Erbin regulates the biological behavior of cancer cells. We report here that depletion of Erbin leads to cancer cell excessive proliferation in vitro and in vivo. Erbin deficiency accelerates S-phase entry by down-regulating CDK inhibitors p21 and p27 via two independent mechanisms. Mechanistically, Erbin loss promotes p27 degradation by enhancing E3 ligase Skp2 activity though augmenting Akt signaling. Interestingly, we also show that Erbin is an unstable protein when the Akt-Skp2 signaling is aberrantly activated, which can be specifically destructed by SCF-Skp2 ligase. Erbin loss facilitates cell proliferation and migration in Skp2-dependent manner. Thus, our finding illustrates a novel negative feedback loop between Erbin and Akt-Skp2 signaling. It suggests disrupted Erbin links polarity loss, hyperproliferation and tumorigenesis.
authors.affiliation: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing 100850, PR China; Laboratory of Cellular and Molecular Immunology, Medical School of Henan University, Kaifeng 475004, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.affiliation: The Affiliated Hospital of Medical College, Qingdao University, Qingdao, PR China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing 100850, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing 100850, PR China.
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Medical School of Henan University, Kaifeng 475004, PR China.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing 100850, PR China. Electronic address: mayf@henu.edu.cn.
authors.forename: Lu
authors.initials: L
authors.lastname: Qian
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C413364:ERBIN protein, human; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Cell proliferation; Erbin; Skp2; Tumorigenesis; p27