SIN1 phosphorylation disrupts mTORC2 and impairs AKT activation in response to various stimuli.
Major finding: SIN1 phosphorylation disrupts mTORC2 and impairs AKT activation in response to various stimuli.
Mechanism: Phosphorylation of both Thr86 and Thr398 by S6K1 or AKT induces SIN1 dissociation from mTORC2.
Impact: Cancer-associated mutations in SIN1 promote hyperactive mTORC2/AKT signaling and tumor growth.
The mTOR pathway functions to promote protein translation and cell growth through two distinct multiprotein complexes, mTORC1 and mTORC2, which phosphorylate the downstream substrates ribosomal protein S6 kinase 1 (S6K1) and AKT, respectively. mTORC1 can negatively regulate mTORC2 activity in part via phosphorylation of insulin receptor substrate 1 (IRS1) and growth factor receptor-bound protein 10 (GRB10), but additional mechanisms by which mTORC1 modulates mTORC2/AKT signaling are incompletely understood. Liu and colleagues found that mTORC1 activation inhibited mTORC2 signaling by promoting phosphorylation of SIN1 (also known as mitogen-activated protein kinase-associated protein 1), a unique and essential component of mTORC2. SIN1 phosphorylation at both Thr86 and Thr398 was cell context dependent and mediated by AKT in adipocytes and largely by S6K1 in epithelial cells. S6K1-driven SIN1 phosphorylation triggered the dissociation of SIN1 from mTORC2 following physiologic stimulation with various growth factors, including insulin, insulin-like growth factor 1, EGF, and platelet-derived growth factor, thereby impairing mTORC2 complex assembly; phosphorylation of both residues was required to disrupt the interaction of SIN1 with Rictor and the mTOR kinase domain. In addition, SIN1 phosphorylation specifically suppressed mTORC2-induced AKT activation and decreased cell viability following treatment with etoposide or cisplatin, supporting a role for S6K1-dependent SIN1 regulation in inhibiting cell survival. Intriguingly, an ovarian cancer–associated mutation in SIN1, Arg81Thr (R81T), attenuated SIN1 phosphorylation at Thr86, resulting in prolonged interaction of SIN1 with mTORC2 and sustained activation of AKT signaling in response to various growth factors. Furthermore, expression of SIN1-R81T enhanced anchorage-independent growth and tumor formation, suggesting that this gain-of-function mutation allows SIN1 to bypass S6K1-dependent inhibition of mTORC2-driven cell proliferation. These results identify a negative feedback mechanism by which mTORC1/S6K1 signaling attenuates mTORC2/AKT activity independently of IRS1 and GRB10, and suggest that dysregulation of SIN1 phosphorylation contributes to tumorigenesis.
Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O, et al. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol 2013;15:1340–50.
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