title: Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors.
abstract: 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 Calpha, 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.
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, Massachusetts General Hospital, Boston, Massachusetts 02115, USA.
authors: Jingxiang
authors: J
authors: Huang
authors: Shulin
authors: S
authors: Wu
authors: Chin-Lee
authors: CL
authors: Wu
authors: Brendan D
authors: BD
authors: Manning
mesh_terms: D018207:Angiomyolipoma / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D002352:Carrier Proteins; D017874:Immediate-Early Proteins; D019869:Phosphatidylinositol 3-Kinases; D051571:Protein Kinase C-alpha; D017346:Protein Serine-Threonine Kinases; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; C493245:CRTC2 protein, human; C492571:RICTOR protein, human; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; C525637:rictor protein, mouse