title: Cycles of ubiquitination and deubiquitination critically regulate growth factor-mediated activation of Akt signaling.
abstract: K63-linked ubiquitination of Akt is a posttranslational modification that plays a critical role in growth factor-mediated membrane recruitment and activation of Akt. Although E3 ligases involved in growth factor-induced ubiquitination of Akt have been defined, the deubiquitinating enzyme (DUB) that triggers deubiquitination of Akt and the function of Akt deubiquitination remain largely unclear. We showed that CYLD was a DUB for Akt and suppressed growth factor-mediated ubiquitination and activation of Akt. CYLD directly removed ubiquitin moieties from Akt under serum-starved conditions. CYLD dissociated from Akt upon growth factor stimulation, thereby allowing E3 ligases to induce ubiquitination and activation of Akt. CYLD deficiency also promoted cancer cell proliferation, survival, glucose uptake, and, when injected into mice, growth of prostate tumors. Our findings reveal the crucial role of cycles of ubiquitination and deubiquitination of Akt in determining its plasma membrane localization and activation--and further identify CYLD as a molecular switch for these processes.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wei-Lei
authors.initials: WL
authors.lastname: Yang
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Jin
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.forename: Yun Seong
authors.initials: YS
authors.lastname: Jeong
authors.forename: Asad
authors.initials: A
authors.lastname: Moten
authors.forename: Dazhi
authors.initials: D
authors.lastname: Xu
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Feng
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cai
authors.forename: Bryant
authors.initials: B
authors.lastname: Darnay
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D000074749:Deubiquitinating Enzyme CYLD; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD