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: Richard C Wang, Yongjie Wei, Zhenyi An, Zhongju Zou, Guanghua Xiao, Govind Bhagat, Michael White, Julia Reichelt, Beth Levine
• Journal: Science (New York, N.Y.) (Science) Vol. 338 Issue 6109 Pg. 956-9 (Nov 16 2012) ISSN: 1095-9203 [Electronic] United States
• PMID: 23112296 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Membrane Proteins
• RNA, Small Interfering
• Vimentin
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy
• Beclin-1
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism)
• Fibroblasts (metabolism, pathology)
• HeLa Cells
• Humans
• Membrane Proteins (genetics, metabolism)
• Mice
• Phosphorylation
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Rats
• Transduction, Genetic
• Vimentin (genetics)
• Xenograft Model Antitumor Assays