Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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:
Autophagy and thyroid carcinogenesis: genetic and epigenetic links.
F. Morani, R. Titone, L. Pagano, A. Galetto, O. Alabiso, G. Aimaretti, and C. Isidoro (2014)
Endocr. Relat. Cancer 21, R13-R29
   Abstract »    Full Text »    PDF »
Phospholipase D2 Mediates Survival Signaling through Direct Regulation of Akt in Glioblastoma Cells.
R. C. Bruntz, H. E. Taylor, C. W. Lindsley, and H. A. Brown (2014)
J. Biol. Chem. 289, 600-616
   Abstract »    Full Text »    PDF »
A Reactive Oxygen Species-Mediated, Self-Perpetuating Loop Persistently Activates Platelet-Derived Growth Factor Receptor {alpha}.
H. Lei and A. Kazlauskas (2014)
Mol. Cell. Biol. 34, 110-122
   Abstract »    Full Text »    PDF »
IGF-1 receptor antagonism inhibits autophagy.
M. Renna, C. F. Bento, A. Fleming, F. M. Menzies, F. H. Siddiqi, B. Ravikumar, C. Puri, M. Garcia-Arencibia, O. Sadiq, S. Corrochano, et al. (2013)
Hum. Mol. Genet. 22, 4528-4544
   Abstract »    Full Text »    PDF »
Mechanism and Physiological Significance of Growth Factor-Related Autophagy.
T. Y. Li, S.-Y. Lin, and S.-C. Lin (2013)
Physiology 28, 423-431
   Abstract »    Full Text »    PDF »
Role of Membrane Association and Atg14-Dependent Phosphorylation in Beclin-1-Mediated Autophagy.
A. I. Fogel, B. J. Dlouhy, C. Wang, S.-W. Ryu, A. Neutzner, S. A. Hasson, D. P. Sideris, H. Abeliovich, and R. J. Youle (2013)
Mol. Cell. Biol. 33, 3675-3688
   Abstract »    Full Text »    PDF »
Down-Regulation of Autophagy-Related Protein 5 (ATG5) Contributes to the Pathogenesis of Early-Stage Cutaneous Melanoma.
H. Liu, Z. He, T. von Rutte, S. Yousefi, R. E. Hunger, and H.-U. Simon (2013)
Science Translational Medicine 5, 202ra123
   Abstract »    Full Text »    PDF »
Autophagy in blood cancers: biological role and therapeutic implications.
A. Nencioni, M. Cea, F. Montecucco, V. D. Longo, F. Patrone, A. M. Carella, T. L. Holyoake, and G. V. Helgason (2013)
Haematologica 98, 1335-1343
   Abstract »    Full Text »    PDF »
Therapeutic Targeting of Autophagy in Disease: Biology and Pharmacology.
Y. Cheng, X. Ren, W. N. Hait, and J.-M. Yang (2013)
Pharmacol. Rev. 65, 1162-1197
   Abstract »    Full Text »    PDF »
Interaction between Her2 and Beclin-1 Proteins Underlies a New Mechanism of Reciprocal Regulation.
J. Han, W. Hou, C. Lu, L. A. Goldstein, D. B. Stolz, S. C. Watkins, and H. Rabinowich (2013)
J. Biol. Chem. 288, 20315-20325
   Abstract »    Full Text »    PDF »
TGF-{beta} Induces Acetylation of Chromatin and of Ets-1 to Alleviate Repression of miR-192 in Diabetic Nephropathy.
M. Kato, V. Dang, M. Wang, J. T. Park, S. Deshpande, S. Kadam, A. Mardiros, Y. Zhan, P. Oettgen, S. Putta, et al. (2013)
Science Signaling 6, ra43
   Abstract »    Full Text »    PDF »
Promoting Tumorigenesis by Suppressing Autophagy.
I. Koren and A. Kimchi (2012)
Science 338, 889-890
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882