SCF β-TRCP -mediated degradation of NEDD4 inhibits tumorigenesis through modulating the PTEN/Akt signaling pathway

摘要: // Jia Liu 1,2,* , Lixin Wan 2,* Pengda Hiroyuki Inuzuka 2 Jiankang 1 Zhiwei Wang 3 and Wenyi Wei Center for Mitochondrial Biology Medicine, The Key Laboratory of Biomedical Information Engineering Ministry Education, School Life Science Technology Frontier Institute Science, FIST, Xi’an Jiaotong University, Xi’an, China Department Pathology, Beth Israel Deaconess Medical Center, Harvard School, Boston, MA Cyrus Tang Hematology Jiangsu Hematology, the First Affiliated Hospital, Soochow Suzhou, Jiangsu, P. R. * These authors contributed equally to this work Correspondence: Wang, email: Wei, Keywords : β-TRCP, NEDD4, degradation, PTEN, Akt, cancer, phosphorylation, ubiquitination, therapy Received December 9, 2013 Accepted January 18, 2014 Published 20, Abstract HECT domain-containing ubiquitin E3 ligase NEDD4 is widely expressed in mammalian tissues plays a crucial role governing wide spectrum cellular processes including cell growth, tissue development homeostasis. Recent reports have indicated that might facilitate tumorigenesis through targeted degradation multiple tumor suppressor proteins PTEN. However, molecular mechanism by which stability regulated has not been fully elucidated. Here we report SCF β-TRCP governs protein targeting it ubiquitination subsequent Casein Kinase-I (CKI) phosphorylation-dependent manner. Specifically, depletion or inactivation CKI, stabilized leading down-regulation its target PTEN activation mTOR/Akt oncogenic pathway. Furthermore, found CKIδ-mediated phosphorylation Ser347 Ser348 on promoted interaction with degradation. As result, compared ectopic expression wild-type introducing non-degradable (S347A/S348A-NEDD4) cancer growth migration. Hence, our findings revealed CKI/SCF signaling axis as upstream negative regulator further suggested enhancing presumably CKI agonists, could be promising strategy treating human cancers.