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

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 15; pp. 6107 - 6114
• Main Authors: JINGXIANG HUANG, SHULIN WU, WU, Chin-Lee, MANNING, Brendan D
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2009
• Subjects: Angiomyolipoma - metabolism; Animals; Antineoplastic agents; Biological and medical sciences; Carrier Proteins - metabolism; Humans; Immediate-Early Proteins - metabolism; Kidney Neoplasms - metabolism; Medical sciences; Mice; Neurology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Protein Kinase C-alpha - metabolism; Protein-Serine-Threonine Kinases - metabolism; Rapamycin-Insensitive Companion of mTOR Protein; Signal Transduction; Transcription Factors - metabolism; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Tumors of the nervous system. Phacomatoses; Signal transduction; Nervous system diseases; Mammalian target of rapamycin; Tumor; Bourneville syndrome; Tumor cell; Genetic disease; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-09-0975

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.