title: Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation.
abstract: Aberrant signaling through the class I phosphatidylinositol 3-kinase (PI3K)-Akt axis is frequent in human cancer. Here, we show that Beclin 1, an essential autophagy and tumor suppressor protein, is a target of the protein kinase Akt. Expression of a Beclin 1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth, and inhibited Akt-driven tumorigenesis. Akt-mediated phosphorylation of Beclin 1 enhanced its interactions with 14-3-3 and vimentin intermediate filament proteins, and vimentin depletion increased autophagy and inhibited Akt-driven transformation. Thus, Akt-mediated phosphorylation of Beclin 1 functions in autophagy inhibition, oncogenesis, and the formation of an autophagy-inhibitory Beclin 1/14-3-3/vimentin intermediate filament complex. These findings have broad implications for understanding the role of Akt signaling and intermediate filament proteins in autophagy and cancer.
authors.affiliation: Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Wang
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Wei
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: An
authors.forename: Zhongju
authors.initials: Z
authors.lastname: Zou
authors.forename: Guanghua
authors.initials: G
authors.lastname: Xiao
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Michael
authors.initials: M
authors.lastname: White
authors.forename: Julia
authors.initials: J
authors.lastname: Reichelt
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014161:Transduction, Genetic; D014746:Vimentin / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D014746:Vimentin; D051057:Proto-Oncogene Proteins c-akt