MTORC2

mTORC2

The mechanistic target of rapamycin complex 2 (mTORC2) is a critical component of the mTOR signaling pathway, which plays a vital role in regulating cell growth, proliferation, survival, and metabolism. mTORC2 is one of two distinct complexes formed by the mTOR kinase, the other being mTORC1. While both complexes share the mTOR kinase, they have unique components and functions.

Structure and Components

mTORC2 is a multi-protein complex composed of several key components:

• mTOR: The central serine/threonine kinase that is shared with mTORC1.
• Rictor (Rapamycin-insensitive companion of mTOR): A defining component of mTORC2 that distinguishes it from mTORC1.
• mLST8 (mammalian lethal with SEC13 protein 8): A protein that associates with both mTORC1 and mTORC2, stabilizing the complexes.
• SIN1 (Stress-activated protein kinase-interacting protein 1): A component that is essential for mTORC2's function and stability.
• Protor1/2 (Protein observed with Rictor 1/2): Proteins that interact with Rictor and are involved in mTORC2 signaling.

Function

mTORC2 is primarily involved in the regulation of the cytoskeleton, cell survival, and metabolism. It is known to phosphorylate several key proteins, including:

• AKT (Protein kinase B): mTORC2 phosphorylates AKT at Ser473, a modification crucial for full activation of AKT, which is involved in cell survival and growth.
• SGK1 (Serum/glucocorticoid-regulated kinase 1): Another kinase activated by mTORC2, involved in ion transport and cell survival.
• PKCα (Protein kinase C alpha): mTORC2 phosphorylates PKCα, influencing cytoskeletal organization and cell migration.

Regulation

mTORC2 activity is regulated by various upstream signals, including growth factors, nutrients, and cellular energy status. Unlike mTORC1, mTORC2 is not acutely sensitive to rapamycin, a drug that specifically inhibits mTORC1. However, prolonged exposure to rapamycin can disrupt mTORC2 assembly in some cell types.

Role in Disease

Dysregulation of mTORC2 has been implicated in several diseases, including:

• Cancer: Aberrant mTORC2 signaling can lead to uncontrolled cell growth and survival, contributing to tumorigenesis.
• Diabetes: mTORC2 plays a role in insulin signaling, and its dysregulation can affect glucose metabolism.
• Neurological Disorders: mTORC2 is involved in neuronal growth and survival, and its dysfunction may contribute to neurodegenerative diseases.

Research and Therapeutic Implications

Understanding mTORC2's role in cellular processes and disease has significant therapeutic potential. Targeting mTORC2, either alone or in combination with mTORC1 inhibitors, is being explored in cancer therapy and other diseases.

Also see

• mTORC1
• AKT signaling pathway
• Rapamycin
• Cell signaling
• Protein kinase