Research Papers:

Association of mSin1 with mTORC2 Ras and Akt reveals a crucial domain on mSin1 involved in Akt phosphorylation

Chien-An Yao, Sara Ortiz-Vega, Yun-Ya Sun, Chiang-Ting Chien, Jen-Hua Chuang and Yenshou Lin _

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Oncotarget. 2017; 8:63392-63404. https://doi.org/10.18632/oncotarget.18818

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Chien-An Yao1,2, Sara Ortiz-Vega3,*, Yun-Ya Sun1, Chiang-Ting Chien1, Jen-Hua Chuang1,** and Yenshou Lin1

1Department of Life Science, National Taiwan Normal University, Taipei, Taiwan

2Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan

3Diabetes Unit and Medical Services and The Department of Molecular Biology, Massachusetts General Hospital and The Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

*Current address: San Juan, PR, Puerto Rico

**Current address: Taipei Veterans General Hospital, Taipei, Taiwan

Correspondence to:

Yenshou Lin, email: [email protected]

Keywords: mSin1, mTORC2, Akt, Ras, association

Received: December 20, 2016     Accepted: June 02, 2017     Published: June 28, 2017


mSin1 is a unique component within the mammalian target of rapamycin (mTOR) complex 2 (mTORC2), which is responsible for cellular morphology and glucose metabolism. The association between mSin1 and other mTORC2 components, as well as their functions, has been explored previously; nevertheless, the mapping of the various binding domains of the components is lacking. Based on an evolutionary analysis of the gene, we constructed various fragments and truncated-forms of mSin1. We characterized the individual binding sites of mSin1 with its various partners, including mTOR, Rictor, Ras, and Akt. mTOR and Rictor bind to the amino acid (aa) 100-240 region of mSin1, which is different to the Ras binding site, the aa 260-460 region. A reciprocal examination found that mSin1 associated with the aa 2148-2300 region of mTOR, which is within the kinase domain, and with the carboxyl terminus of Rictor. Interestingly, Akt was found to associate with mSin1 in a region that slightly overlapped with the mTOR/Rictor complex binding site, namely aa 220-260. When only the Akt binding site was deleted from mSin1, phosphorylation of Akt S473 was greatly reduced. Furthermore, the association between Akt and mTOR can be regulated by serum, insulin and LY294002, but not by rapamycin or MAPK kinase inhibitors. Taken together, mSin1 would seem to act as a hub that allows mTORC2 to phosphorylate Akt S473. Our findings should facilitate future proteomic and crystallographic studies, help the development of dominant inhibitors and promote the identification of new drug targets.

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