Mammalian TOR signaling to the AGC kinases

Abstract

The mechanistic (or mammalian) target of rapamycin (mTOR), an evolutionarily conserved protein kinase, orchestrates cellular responses to growth, metabolic and stress signals. mTOR processes various extracellular and intracellular inputs as part of two mTOR protein complexes, mTORC1 or mTORC2. The mTORCs have numerous cellular targets but members of a family of protein kinases, the protein kinase (PK)A/PKG/PKC (AGC) family are the best characterized direct mTOR substrates. The AGC kinases control multiple cellular functions and deregulation of many members of this family underlies numerous pathological conditions. mTOR phosphorylates conserved motifs in these kinases to allosterically augment their activity, influence substrate specificity, and promote protein maturation and stability. Activation of AGC kinases in turn triggers the phosphorylation of diverse, often overlapping, targets that ultimately control cellular response to a wide spectrum of stimuli. This review will highlight recent findings on how mTOR regulates AGC kinases and how mTOR activity is feedback regulated by these kinases. We will discuss how this regulation can modulate downstream targets in the mTOR pathway that could account for the varied cellular functions of mTOR.

Keywords::

• mTOR
• AGC kinases
• Sin1
• rictor
• Akt
• mTOR complexes
• mTORC1
• mTORC2

Acknowledgements

We thank the members of Su and Jacinto laboratories for helpful discussions and comments on this manuscript, and Ms. Rong Tan for help with figure illustration.

Declaration of interest

The authors report no declarations of interest. This work was supported in part by grants from NIH (AI063348) and DOD (PR093728) to BS, and the American Cancer Society RSG0721601TBE, Cancer Research Institute and NIH (GM079176) to EJ.

Editor: Michael M. Cox