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:
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.
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.
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.
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.
Examples:
TC#	Name	Organismal Type	Example
8.A.188.1.1	RICTOR/mTORC2 of 1708 aas. 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, it 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' and also modulates the phosphorylation of PRKCA on 'Ser-657'. It plays an essential role in embryonic growth and development.		Rictor of Homo sapiens

8.A.188.1.10	Uncharacterized protein of 1165 aas and 2 possible TMSs.		UP of Stentor coeruleus

8.A.188.1.2	Uncharacterized protein of 1288 aas and 2 possible centrally located TMSs.		UP of Aureobasidium pullulans

8.A.188.1.3	Uncharacterized protein of 1026 aas and 0 - 4 centrally located TMSs.		UP of Pomphorhynchus laevis

8.A.188.1.4	Uncharacterized protein of 1170 aas and 0 TMSs.		UP of Schistosoma bovis

8.A.188.1.5	Uncharacterized protein of 1282 aas and 0 TMSs		UP of Aphanomyces invadans

8.A.188.1.6	Putative TORC2 complex subunit of 1261 aas and 0 TM		TORC2 complex subunit of Clavispora lusitaniae

8.A.188.1.7	Uncharacterized protein of 1988 aas		UP of Hydatigera taeniaeformis

8.A.188.1.8	Cytosolic regulator Pianissimo of 839 aas and 2 TM		Pianissimo of Reticulomyxa filosa

8.A.188.1.9	Uncharacterized protein of 1321 aas and possibly 2 TMSs.		UP of Monosiga brevicollis