mTORC2

mTORC2 (mechanistic target of rapamycin complex 2) is a multi-protein complex that constitutes one of two distinct mTOR signaling complexes. It regulates cell survival, cytoskeletal organization, metabolism, and other processes by phosphorylating a subset of AGC kinases, most notably AKT at serine 473. In mammals, mTORC2's core components are mTOR kinase, RICTOR (rapamycin-insensitive companion of mTOR), and mLST8 (GβL). Accessory subunits MAPKAP1 (mSIN1), and PRR5/PRR5L (Protor-1/2) contribute to complex stability and substrate selection.

Activation and localization: mTORC2 assembly requires RICTOR and mLST8; complex activity is stimulated by growth factor signaling via PI3K, and by cues that affect the actin cytoskeleton and cell adhesion. Unlike mTORC1, mTORC2 is relatively resistant to acute rapamycin treatment; chronic exposure in some cells can prevent assembly, thereby reducing activity. The complex localizes to the cytosol and plasma membrane, particularly at sites enriched in PI3K-generated lipids.

Downstream actions: The principal substrate of mTORC2 is AKT, phosphorylating Ser473 to facilitate full activation by PDK1. Other targets include PKCα and SGK1, influencing cytoskeletal remodeling, cell survival, glucose and lipid metabolism. Through these actions, mTORC2 integrates growth factor signals with cellular architecture and metabolic programs.

Clinical and research notes: Dysregulation of mTORC2 signaling has been implicated in cancer, metabolic disease, and aging-related disorders. The pathway is a focus of therapeutic exploration, with attention to its role in AKT signaling and compensatory feedback upon mTORC1 inhibitors.