The Roles of Post-Translational Modifications on mTOR Signaling

Abstract

The mechanistic target of rapamycin (mTOR) is a master regulator of cell growth, proliferation, and metabolism by integrating various environmental inputs including growth factors, nutrients, and energy, among others. mTOR signaling has been demonstrated to control almost all fundamental cellular processes, such as nucleotide, protein and lipid synthesis, autophagy, and apoptosis. Over the past fifteen years, mapping the network of the mTOR pathway has dramatically advanced our understanding of its upstream and downstream signaling. Dysregulation of the mTOR pathway is frequently associated with a variety of human diseases, such as cancers, metabolic diseases, and cardiovascular and neurodegenerative disorders. Besides genetic alterations, aberrancies in post-translational modifications (PTMs) of the mTOR components are the major causes of the aberrant mTOR signaling in a number of pathologies. In this review, we summarize current understanding of PTMs-mediated regulation of mTOR signaling, and also update the progress on targeting the mTOR pathway and PTM-related enzymes for treatment of human diseases.

Keywords: human diseases; inhibitors; mTOR; post-translational modifications.

Figure 1

Core components of mTORC1 and mTORC2 complexes. mTOR and mLST8 are two shared subunits. Raptor defines the mTORC1 complex, while Rictor and Sin1 define mTORC2. DEPTOR is an endogenous inhibitor of both mTORC1 and mTORC2 complexes.

Figure 2

Amino acids and growth factors-mediated activation of the mTORC1 signaling. Amino acids bind to their specific sensors and transduce the signal through GATOR2, GATOR1, KICSTOR, and Ragulator complexes, leading to activation of Rag small GTPases and lysosomal recruitment of mTORC1. Growth factors activate other lysosomal localized small GTPases Rheb through Akt/TSC signaling axis. The small GTPases Rags and Rheb form two arms to fully activate mTORC1 pathway in response to amino acids and growth factors.

Figure 3

Crosstalk between mTOR signaling and PI3K/Akt pathway. Growth factors bind to receptor tyrosine kinase (RTK) and activate PI3K to convert PIP2 to PIP3, which can be reversed by PTEN. PIP3 recruits Akt to the plasma membrane for phosphorylation at T308 and S473 by PDK1 and mTORC2, respectively. Activated Akt suppresses TSC complex to promote GTP loading on Rheb for mTORC1 activation. In turn, mTORC1 phosphorylates Grb10 to inhibit RTK/PI3K activity. Thus, PI3K, Akt, and mTOR form a feedback regulatory loop.