mTORC2s

mTORC2s, or mTOR complexes 2, denote the rapamycin-insensitive class of the mechanistic target of rapamycin signaling complexes. In mammals the assembly centers on the kinase mTOR and the regulator Rictor, together with the scaffolding protein mLST8 (GβL). Additional regulatory subunits, including mSIN1 (SIN1) and Protor1/2, modulate activity and substrate selection. The complex also binds the negative regulator DEPTOR. In yeast and other organisms, TORC2 plays a role in organizing the cytoskeleton, while in mammals it phosphorylates multiple AGC kinases, notably AKT at Ser473, SGK1, and PKCα, thereby influencing survival, metabolism, and cytoskeletal dynamics.

mTORC2s are activated downstream of growth factor signaling via PI3K and are thought to be recruited and activated at membranes and at ribosomes; the precise triggers are still studied. The complex is largely insensitive to acute rapamycin exposure, though prolonged treatment can disrupt assembly in some contexts. Through AKT Ser473 phosphorylation, mTORC2s promote cell survival and growth; via PKC and SGK, they influence cytoskeletal organization, trafficking, and ion transport.

Disruption or dysregulation of mTORC2 signaling has been linked to cancer, metabolic disorders, and degenerative diseases. Because of its central role, researchers study inhibitors of the mTOR kinase that affect both complexes and explore compounds that preferentially target mTORC2. The composition of mTORC2s can vary in different tissues, reflecting regulatory inputs that tailor signaling outputs.