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  A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation

Yang, G., Murashige, D. S., Humphrey, S. J., & James, D. E. (2015). A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation. CELL REPORTS, 12(6), 937-943. doi:10.1016/j.celrep.2015.07.016.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-463C-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-463D-9
Genre: Journal Article

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 Creators:
Yang, Guang1, Author
Murashige, Danielle S.1, Author
Humphrey, Sean J.2, Author              
James, David E.1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: TURN MOTIF PHOSPHORYLATION; PROTEIN-KINASE 1; COMPLEX 2 MTORC2; PHOSPHOPROTEOME REVEALS; AGC KINASES; RICTOR; ACTIVATION; MECHANISM; MOUSE; CELL
 Abstract: The mechanistic target of rapamycin complex 2 (mTORC2) regulates cell survival and cytoskeletal organization by phosphorylating its AGC kinase substrates; however, little is known about the regulation of mTORC2 itself. It was previously reported that Akt phosphorylates the mTORC2 subunit SIN1 at T86, activating mTORC2 through a positive feedback loop, though another study reported that S6K phosphorylates SIN1 at the same site, inhibiting mTORC2 activity. We performed extensive analysis of SIN1 phosphorylation upon inhibition of Akt, S6K, and mTOR under diverse cellular contexts, and we found that, in all cell lines and conditions studied, Akt is the major kinase responsible for SIN1 phosphorylation. These findings refine the activation mechanism of the Akt-mTORC2 signaling branch as follows: PDK1 phosphorylates Akt at T308, increasing Akt kinase activity. Akt phosphorylates SIN1 at T86, enhancing mTORC2 kinase activity, which leads to phosphorylation of Akt S473 by mTORC2, thereby catalyzing full activation of Akt.

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Language(s): eng - English
 Dates: 2015
 Publication Status: Published in print
 Pages: 7
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Degree: -

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Title: CELL REPORTS
Source Genre: Journal
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Publ. Info: 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA : CELL PRESS
Pages: - Volume / Issue: 12 (6) Sequence Number: - Start / End Page: 937 - 943 Identifier: ISSN: 2211-1247