Research Papers:

Rapamycin inhibits mSin1 phosphorylation independently of mTORC1 and mTORC2

Yan Luo _, Lei Liu, Yang Wu, Karnika Singh, Bing Su, Nan Zhang, Xiaowei Liu, Yangmei Shen and Shile Huang

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Oncotarget. 2015; 6:4286-4298. https://doi.org/10.18632/oncotarget.3006

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Yan Luo1,2,3,*, Lei Liu2,*, Yang Wu1,2, Karnika Singh2, Bing Su4, Nan Zhang1, Xiaowei Liu1, Yangmei Shen1, Shile Huang2,3

1State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China

2Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

3Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA

4Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

*These authors have contributed equally to this work

Correspondence to:

Shile Huang, e-mail: [email protected]

Keywords: Rapamycin, mTOR, mSin1, raptor, rictor

Received: November 19, 2014     Accepted: December 21, 2014     Published: January 30, 2015


Current knowledge indicates that the mammalian target of rapamycin (mTOR) functions as two complexes, mTORC1 and mTORC2, regulating cell growth, proliferation, survival, differentiation, and motility. Recently mSin1 has been identified as a critical component of mTORC2, which is essential for phosphorylation of Akt and other signaling molecules. Studies have shown that rapamycin inhibits phosphorylation of mSin1. However, the underlying mechanism is unknown. Here we found that rapamycin inhibited phosphorylation of mSin1 potently and rapidly. Expression of rapamycin-resistant mutant of mTOR (mTOR-T), but not rapamycin-resistant and kinase dead mutant of mTOR (mTOR-TE), prevented rapamycin from inhibiting mSin1 phosphorylation, suggesting that rapamycin-induced dephosphorylation of mSin1 is mTOR-dependent. Surprisingly, ectopic expression of rapamycin-resistant and constitutively active p70 S6 kinase 1 (S6K1) did not confer resistance to rapamycin-induced dephosphorylation of mSin1. Furthermore, disruption of mTORC1 and mTORC2 by silencing raptor and rictor, respectively, or downregulation of S6K1 or Akt did not induce the dephosphorylation of mSin1 as rapamycin did. However, silencing mTOR or mLST8 mimicked the effect of rapamycin, inhibiting mSin1 phosphorylation. Our findings suggest that rapamycin inhibits mSin1 phosphorylation, which is independent of mTORC1 and mTORC2, but is possibly dependent on a new mTOR complex, which at least contains mTOR and mLST8.

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