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Signaling Events Downstream of Mammalian Target of Rapamycin Complex 2 Are Attenuated in Cells and Tumors Deficient for the Tuberous Sclerosis Complex Tumor Suppressors

¹ Department of Genetics and Complex Diseases, Harvard School of Public Health; ² Urologic Research Laboratory, Massachusetts General Hospital, Department of Pathology, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Brendan D. Manning, Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, SPH2-117, Boston, MA 02115. Phone: 617-432-5614; Fax: 617-432-5236; E-mail: bmanning{at}hsph.harvard.edu.

Key Words: mTOR • TSC2 • tuberous sclerosis

Mutations in the TSC1 and TSC2 tumor suppressor genes give rise to the neoplastic disorders tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis. Their gene products form a complex that is a critical negative regulator of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and cell growth. We recently found that the TSC1-TSC2 complex promotes the activity of mTOR complex 2 (mTORC2), an upstream activator of Akt, and this occurs independent of its inhibitory effects on mTORC1. Loss of mTORC2 activity in cells lacking the TSC1-TSC2 complex, coupled with mTORC1-mediated feedback mechanisms, leads to strong attenuation of the growth factor–stimulated phosphorylation of Akt on S473. In this study, we show that both phosphatidylinositol 3-kinase–dependent and phosphatidylinositol 3-kinase–independent mTORC2 substrates are affected by loss of the TSC1-TSC2 complex in cell culture models and kidney tumors from both Tsc2^+/- mice (adenoma) and TSC patients (angiomyolipoma). These mTORC2 targets are all members of the AGC kinase family and include Akt, protein kinase C, and serum and glucocorticoid-induced protein kinase 1. We also show that the TSC1-TSC2 complex can directly stimulate the in vitro kinase activity of mTORC2. The interaction between these two complexes is mediated primarily through regions on TSC2 and a core component of mTORC2 called Rictor. Hence, loss of the TSC tumor suppressors results in elevated mTORC1 signaling and attenuated mTORC2 signaling. These findings suggest that the TSC1-TSC2 complex plays opposing roles in tumor progression, both blocking and promoting specific oncogenic pathways through its effects on mTORC1 inhibition and mTORC2 activation, respectively. [Cancer Res 2009;69(15):6107–14]