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FUNCTION Component of the mechanistic target of rapamycin complex 2 (mTORC2), which transduces signals from growth factors to pathways involved in proliferation, cytoskeletal organization, lipogenesis and anabolic output (PubMed:15467718, PubMed:16919458, PubMed:16962653, PubMed:17043309, PubMed:21806543, PubMed:28264193, PubMed:28968999, PubMed:30837283, PubMed:35926713). In response to growth factors, mTORC2 phosphorylates and activates AGC protein kinase family members, including AKT (AKT1, AKT2 and AKT3), PKC (PRKCA, PRKCB and PRKCE) and SGK1 (PubMed:16919458, PubMed:16962653, PubMed:21806543, PubMed:28264193, PubMed:28968999, PubMed:30837283, PubMed:35926713). In contrast to mTORC1, mTORC2 is nutrient-insensitive (PubMed:16962653). Within the mTORC2 complex, MAPKAP1/SIN1 acts as a substrate adapter which recognizes and binds AGC protein kinase family members for phosphorylation by MTOR (PubMed:21806543, PubMed:28264193). mTORC2 plays a critical role in AKT1 activation by mediating phosphorylation of different sites depending on the context, such as 'Thr-450', 'Ser-473', 'Ser-477' or 'Thr-479', facilitating the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDPK1/PDK1 which is a prerequisite for full activation (PubMed:28264193, PubMed:35926713). mTORC2 catalyzes the phosphorylation of SGK1 at 'Ser-422' and of PRKCA on 'Ser-657' (PubMed:30837283, PubMed:35926713). The mTORC2 complex also phosphorylates various proteins involved in insulin signaling, such as FBXW8 and IGF2BP1 (By similarity). mTORC2 acts upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors (PubMed:15467718). mTORC2 promotes the serum-induced formation of stress-fibers or F-actin (PubMed:15467718). MAPKAP1 inhibits MAP3K2 by preventing its dimerization and autophosphorylation (PubMed:15988011). Inhibits HRAS and KRAS independently of mTORC2 complex (PubMed:17303383, PubMed:34380736, PubMed:35522713). Enhances osmotic stress-induced phosphorylation of ATF2 and ATF2-mediated transcription (PubMed:17054722). Involved in ciliogenesis, regulates cilia length through its interaction with CCDC28B independently of mTORC2 complex (PubMed:23727834).FUNCTION In contrast to isoform 1, isoform 2 and isoform 6, isoform 4 is not a component of the a mTORC2 complex.ACTIVITY REGULATION Phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) promotes MTOR activation by relieving MAPKAP1/SIN1-mediated inhibition of MTOR that takes place in absence of PI(3,4,5)P3.SUBUNIT Component of the mechanistic target of rapamycin complex 2 (mTORC2), consisting in two heterotretramers composed of MTOR, MLST8, RICTOR and MAPKAP1/SIN1 (PubMed:16919458, PubMed:16962653, PubMed:28264193, PubMed:29424687, PubMed:29567957, PubMed:33378666, PubMed:34519268, PubMed:35926713). The mTORC2 core complex associates with PRR5/PROTOR1 and/or PRR5L/PROTOR2 (PubMed:29424687). Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin (PubMed:15467718). Interacts with MAP3K2 (PubMed:15988011). Interacts with ATF2 (PubMed:17054722). Interacts with MAPK8 (PubMed:17054722). Interacts with GTP-bound HRAS and KRAS; inhibiting their activity (PubMed:17303383, PubMed:34380736, PubMed:35522713). Interacts with IFNAR2 (By similarity).SUBUNIT Interacts with CCDC28B.SUBUNIT Interacts with NBN.INTERACTION The mTORC2 complex localizes to membranes: mTORC2 is active at the plasma membrane, endoplasmic reticulum membrane, lysosomes and perinuclear region (PubMed:17303383, PubMed:21867682, PubMed:30837283). Iin lysosomal membrane, mTORC2 is sensitive to lysosomal positioning in the cell (PubMed:31130364). Following phosphorylation by PKC, localizes to the perinuclear region, where the mTORC2 complexe specifically phosphorylates SGK1, but not AKT (PubMed:30837283).SUBCELLULAR LOCATION Ubiquitously expressed, with highest levels in heart and skeletal muscle.DOMAIN The CRIM domain forms a ubiquitin-like fold with a characteristic acidic loop, which recognizes and binds AGC protein kinase family members substrates.DOMAIN Arg-83 is required for the phosphorylation of SGK1, but not AKT (AKT1, AKT2 and AKT3): SGK1 promotes a large conformation change of the N-terminus of MAPKAP1/SIN1, promoting formation of a salt-bridge with RICTOR, leading to SGK1 phosphorylation.DOMAIN The SIN1-type PH binds phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) (PubMed:26293922). It plays a dual role in mTORC2: in absence of PI(3,4,5)P3, it binds and inactivates MTOR (PubMed:26293922). PI(3,4,5)P3-binding relieves the inhibition, leading to mTORC2 activation (PubMed:26293922).PTM Phosphorylation at Ser-128 by PKC promotes relocalization to the perinuclear region, where the mTORC2 complex specifically mediates phosphorylation of SGK1 (By similarity). Phosphorylated at Thr-86 by AKT1 or RPS6KB1 in the presence of growth factors; the effect of this phosphorylation is however unclear (By similarity). According to two studies, phosphorylation at Thr-86 by AKT1 is part of a positive feedback loop that increases mTORC2 activation (By similarity). According to another study, phosphorylation at Thr-86 and Thr-398 by RPS6KB1 promotes dissociation from the mTORC2 complex, leading to inhibit mTORC2 signaling (By similarity).SIMILARITY Belongs to the SIN1 family.
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