Growth Factor-Dependent and -Independent Activation of mTORC2

The target of rapamycin complex 2 (TORC2) was discovered in 2002 in budding yeast. Its mammalian counterpart, mTORC2, was first described in 2004. Soon thereafter it was demonstrated that mTORC2 directly phosphorylates Akt on Ser473, ending a long search for the elusive ‘second’ insulin-responsive Akt kinase. In this review we discuss key evidence pertaining to the subcellular localization of mTORC2, highlighting a spatial heterogeneity that relates to mTORC2 activation. We summarize current models for how growth factors (GFs), such as insulin, trigger mTORC2 activation, and we provide a comprehensive discussion focusing on a new exciting frontier, the molecular mechanisms underpinning GF-independent activation of mTORC2. Different versions of mTORC2 are located in different subcellular compartments, allowing versatile signaling sensing and transduction.In addition to activation by classical GFs, mTORC2 can be activated by GF-independent mechanisms.GF-independent mTORC2 activation comprises adrenergic agonists, lipid species, exercise and possibly acetylation.The phosphorylation state of Akt Ser473, a good proxy for GF-dependent activation of mTORC2, is a poor readout for assessing GF-independent mTORC2 activity.