Regulation of the Mechanistic Target of Rapamycin by Cellular Stress.

Abstract

In complex eukaryotes, cell, tissue, and organismal homeostasis requires proper sensing of growth factors and nutrients. The mechanistic target of rapamycin (mTOR) functions as a central integrator of diverse cellular stimuli to regulate fundamental cellular processes. mTOR, a serine/threonine protein kinase, forms the catalytic core of at least two distinct signaling complexes, the raptor-associated mTOR complex 1 (mTORC1) and the rictor-associated mTOR complex 2 (mTORC2). Growth factors and nutrients activate mTORC1 to promote anabolic processes including protein and lipid biosynthesis, cell growth, and cell proliferation. mTORC1 dysregulation contributes to insulin resistance, type 2 diabetes, tumorigenesis, and neurodegenerative disorders. mTORC2 responds to insulin signaling and is important for glucose homeostasis and cell survival. The regulation and function of mTORC2 is not well understood. We have found that mTORC1 is regulated by phosphorylation of mTOR, yet the upstream pathways that control this phosphorylation and the role of mTOR phosphorylation in mTORC2 are unclear. My research has uncovered a novel mTOR regulatory mechanism whereby cellular stress promotes mTOR phosphorylation and regulates both mTORC1 and mTORC2 signaling. I expect these results to shed light on the regulation of mTOR and provide the rationale for targeting mTOR and stress pathways upstream of mTOR in the treatment of metabolic disorders.