mTORC2

mTOR Complex 2 (mTORC2) is a protein complex that regulates cellular metabolism as well as the cytoskeleton. It is defined by the interaction of mTOR and the rapamycin-insensitive companion of mTOR (RICTOR), and also includes GβL, mammalian stress-activated protein kinase interacting protein 1 (mSIN1), as well as Protor 1/2, DEPTOR, and TTI1 and TEL2. mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα). mTORC2 also regulates cellular proliferation and metabolism, in part through the regulation of IGF-IR, InsR, Akt/PKB and the serum-and glucocorticoid-induced protein kinase SGK. mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB at a serine residue S473 as well as serine residue S450. Phosphorylation of the serine stimulates Akt phosphorylation at a threonine T308 residue by PDK1 and leads to full Akt activation. Curcumin inhibits both by preventing phosphorylation of the serine. Moreover, mTORC2 activity has been implicated in the regulation of autophagy(macroautophagy and chaperone mediated autophagy). In addition, mTORC2 has tyrosine kinase activity and phosphorylates IGF-IR and insulin receptor at the tyrosine residues Y1131/1136 and Y1146/1151, respectively, leading to full activation of IGF-IR and InsR. mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels. Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation. However, subsequent studies have shown that, at least in some cell lines, chronic exposure to rapamycin, while not affecting pre-existing mTORC2s, promotes rapamycin inhibition of free mTOR molecules, thus inhibiting the formation of new mTORC2. mTORC2 can be inhibited by chronic treatment with rapamycin in vivo, both in cancer cells and normal tissues such as the liver and adipose tissue. Torin1 can also be used to inhibit mTORC2. Localization of mTORC2 in the cell has been suggested to be at the plasma membrane; however, this may be due to its association with Akt. mTORC2 activation has thought to be due to growth factors, given that it regulates the activity of Akt and PKC. mTORC2 may play a role in cancer, given its regulation of the widely studied oncogenetic Akt pathway. Chronic mTORC2 activity may play a role in systemic lupus erythematosus by impairing lysosome function. Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.