mTORC2

mTOR
Identifiers
Symbol	MTOR
Alt. symbols	FRAP, FRAP2, FRAP1
Entrez	2475
HUGO	3942
OMIM	601231
RefSeq	NM_004958
UniProt	P42345
Other data
EC number	2.7.11.1
Locus	Chr. 1 p36

RICTOR
Identifiers
Symbol	RICTOR
Entrez	253260
HUGO	28611
RefSeq	NM_152756
Other data
Locus	Chr. 5 p13.1

MLST8
Identifiers
Symbol	MLST8
Entrez	64223
HUGO	24825
OMIM	612190
RefSeq	NM_022372
UniProt	Q9BVC4
Other data
Locus	Chr. 16 p13.3

MAPKAP1
Identifiers
Symbol	MAPKAP1
Entrez	79109
HUGO	18752
OMIM	610558
RefSeq	NM_001006617.1
UniProt	Q9BPZ7
Other data
Locus	Chr. 9 q34.11

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.

Function

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 metabolism, in part through the regulation of 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.

Regulation

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.

Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.

Studies using mice with tissue-specific loss of Rictor, and thus inactive mTORC2, have found that mTORC2 plays a critical role in the regulation of glucose homeostasis. Liver-specific disruption of mTORC2 through hepatic deletion of the gene Rictor leads to glucose intolerance, hepatic insulin resistance, decreased hepatic lipogenesis, and decreased male lifespan. Adipose-specific disruption of mTORC2 through deletion of Rictor may protect from a high-fat diet in young mice, but results in hepatic steatosis and insulin resistance in older mice. Loss of mTORC2/Rictor in pancreatic beta cells results in reduced beta cell mass and insulin secretion, and hyperglycemia and glucose intolerance.

External links

• TOR complex 2 at the US National Library of Medicine Medical Subject Headings (MeSH)}