mTOR complex 2 signaling and functions

Abstract

The mechanistic target of rapamycin (mTOR) plays a central role in cellular growth and metabolism. mTOR forms two distinct protein complexes, mTORC1 and mTORC2. Much is known about the regulation and functions of mTORC1 due to availability of a natural compound, rapamycin, that inhibits this complex. Studies that define mTORC2 cellular functions and signaling have lagged behind. The development of pharmacological inhibitors that block mTOR kinase activity, and thereby inhibit both mTOR complexes, along with availability of mice with genetic knockouts in mTOR complex components have now provided new insights on mTORC2 function and regulation. Since prolonged effects of rapamycin can also disrupt mTORC2, it is worth re-evaluating the contribution of this less-studied mTOR complex in cancer, metabolic disorders and aging. In this review, we focus on recent developments on mammalian mTORC2 signaling mechanisms and its cellular and tissue-specific functions.

Figure 1

mTORC2 components, interactors and upstream regulators (A) mTORC2, consisting of the core components, mTOR, rictor, SIN1, mLST8, responds to the presence of growth signals. It associates with the large subunit of ribosomes. mTORC2 also associates with other less-conserved proteins that could regulate specific functions of mTORC2. (B) Rictor and SIN1 associates with other proteins independently of mTORC2. Positive regulators are shaded in green, while negative regulators are in red. TSC1/2, a negative regulator of mTORC1, was shown to be required for mTORC2 activity, hence is also shown in green.

Figure 2

Functions and downstream targets of mTORC2. mTORC2 functions in a number of cellular processes by mediating the phosphorylation of conserved motifs in AGC kinases to promote their maturation, stability and allosteric activation. Phosphorylation sites that are targeted by mTORC2, mainly in the turn or hydrophobic motifs, are indicated. Catalytic activation of these AGC kinases requires phosphorylation of the activation loop by PDK1 (not shown here). In the absence of Ser473 phosphorylation, Akt can still phosphorylate some of its substrates, such as TSC2 and GSK3. AGC kinases phosphorylate a multitude of substrates that mediate numerous cellular functions. The functions of mTORC2 indicated here promote cell growth. Whether mTORC2 can play a role in cellular and organismal aging via regulation of AGC kinases or other substrates remains to be elucidated.

Figure 3

Tissue-specific functions of mTORC2. Genetic knockouts have revealed functions of mTORC2 in specific tissues or organs in mice.