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Science 338 (6109): 956-959

Copyright © 2012 by the American Association for the Advancement of Science

Akt-Mediated Regulation of Autophagy and Tumorigenesis Through Beclin 1 Phosphorylation

Richard C. Wang,1,2 Yongjie Wei,2,3,4 Zhenyi An,2,3 Zhongju Zou,2,3,4 Guanghua Xiao,5 Govind Bhagat,6 Michael White,7 Julia Reichelt,8 Beth Levine2,3,4,9,*

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.

1 Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2 Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5 Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6 Department of Pathology and Cell Biology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY 10032, USA.
7 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
8 Institute of Cellular Medicine, University of Newcastle, Framlington Place, NE2 4HH Newcastle upon Tyne, UK.
9 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

* To whom correspondence should be addressed. E-mail: beth.levine{at}utsouthwestern.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Promoting Tumorigenesis by Suppressing Autophagy.
I. Koren and A. Kimchi (2012)
Science 338, 889-890
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