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Disruption of scaffolding function of mLST8 selectively inhibits mTORC2 assembly and function and suppresses mTORC2-dependent tumor growth in vivo


Hwang Y , Kim LC , Song W , Edwards DN , Cook RS , Chen J , . Cancer research. 2019 5 13; ().


Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that acts in two distinct complexes, mTORC1 and mTORC2, and is dysregulated in many diseases including cancer. mLST8 is a shared component of both mTORC1 and mTORC2, yet little is known regarding how mLST8 contributes to assembly and activity of the mTOR complexes. Here we assessed mLST8 loss in a panel of normal and cancer cells and observed little to no impact on assembly or activity of mTORC1. However, mLST8 loss blocked mTOR association with mTORC2 cofactors Rictor and Sin1 and impaired mTORC2 kinase activity, including phosphorylation of AKT at S473. Simultaneous mutation of two pairs of amino acids within mLST8 disrupted its interactions with mTOR and blocked mTOR assembly with Rictor and Sin1, thus abrogating mTORC2 activity. Similarly, a single pair of mutations on mLST8 with a corresponding mutation on mTOR interfered with mTORC2 assembly and activity without affecting mTORC1. We also discovered a direct interaction between mLST8 and the NH2-terminal domain of the mTORC2 co-factor Sin1. In PTEN-null prostate cancer xenografts, mLST8 mutations disrupting the mTOR interaction motif inhibited AKT S473 phosphorylation and decreased tumor cell proliferation and tumor growth in vivo. Together these data suggest that the scaffolding function of mLST8 is critical for assembly and activity of mTORC2, but not mTORC1, an observation which could enable mTORC2-selective inhibition as a therapeutic strategy.