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8.A.188.  The Rictor/mTORC2 (Rictor) Family 

Rictor is a key component of the mammalian target of rapamycin complex 2 (mTORC2) and is required for Akt phosphorylation on Ser473. Wang et al. 2021 showed that knockdown of Rictor prevents cardiomyocyte differentiation from mouse embryonic stem (ES) cells and induces abnormal electrophysiology of ES cell-derived cardiomyocytes (ESC-CMs). Besides, knockdown of Rictor causes down-expression of connexin 43 (Cx43), the predominant gap junction protein, that is located in both the sarcolemma and mitochondria in cardiomyocytes. Mitochondrial Cx43 (mtCx43) plays a crucial role in mitochondrial function. Wang et al. 2021 used the model of cardiomyocyte differentiation from mouse ES cells to elucidate the mechanisms for the mitochondrial damage in ESC-CMs after knockdown of Rictor. They showed that swollen and ruptured mitochondria were observed after knockdown of Rictor under transmission electron microscope. ATP production and the mitochondrial transmembrane potential were decreased in Rictor-knockdown cells, and knockdown of Rictor inhibited the activities of the mitochondrial respiratory chain complex. The above-mentioned changes were linked to inhibiting the translocation of Cx43 into mitochondria upon knockdown of Rictor. Knockdown of Rictor inactivated the mTOR/Akt signalling pathway and subsequently decreased HDAC6 expression, resulting in Hsp90 hyper-acetylation caused by HDAC6 inhibition, and inhibited the formation of the Hsp90-Cx43-TOM20 complex. Thus, the mitochondrial Cx43 participates in shRNA-Rictor-induced mitochondrial functional damage in the ESC-CMs (Wang et al. 2021).

As noted above, Rictor is a subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors (Sarbassov et al. 2004). mTORC2 promotes the serum-induced formation of stress-fibers or F-actin (Jacinto et al. 2004). mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation (Sarbassov et al. 2005). mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. It plays an essential role in embryonic growth and development.

References associated with 8.A.188 family:

Jacinto, E., R. Loewith, A. Schmidt, S. Lin, M.A. Rüegg, A. Hall, and M.N. Hall. (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6: 1122-1128. 15467718
Sarbassov, D.D., D.A. Guertin, S.M. Ali, and D.M. Sabatini. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098-1101. 15718470
Sarbassov, D.D., S.M. Ali, D.H. Kim, D.A. Guertin, R.R. Latek, H. Erdjument-Bromage, P. Tempst, and D.M. Sabatini. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14: 1296-1302. 15268862
Wang, J.D., Y. Shao, D. Liu, N.Y. Liu, and D.Y. Zhu. (2021). Rictor/mTORC2 involves mitochondrial function in ES cells derived cardiomyocytes via mitochondrial Connexin 43. Acta Pharmacol Sin 42: 1790-1797. 33547375