mTOR: A Cellular Regulator Interface in Health and Disease

Abstract

The mechanistic target of Rapamycin (mTOR) is a ubiquitously-conserved serine/threonine kinase, which has a central function in integrating growth signals and orchestrating their physiologic effects on cellular level. mTOR is the core component of differently composed signaling complexes that differ in protein composition and molecular targets. Newly identified classes of mTOR inhibitors are being developed to block autoimmune diseases and transplant rejections but also to treat obesity, diabetes, and different types of cancer. Therefore, the selective and context-dependent inhibition of mTOR activity itself might come into the focus as molecular target to prevent severe diseases and possibly to extend life span. This review provides a general introduction to the molecular composition and physiologic function of mTOR complexes as part of the Special Issue "2018 Select Papers by Cells' Editorial Board Members".

Keywords: aging; autophagy; cancer; kinase; mTOR; phosphorylation.

Figure 1

Cellular functions of TORC1 and TORC2. Growth factors activate both TORC1 and TORC2. Moreover, TORC1 integrates information concerning oxygen concentration, amino acid availability and changing energy levels, while it is inhibited by cellular stress and rapamycin. TORC1 supports translation, cell cycle, and cellular metabolism, while it inhibits autophagy. TORC2 controls cellular metabolism and cytoskeleton dynamics.

Figure 2

Composition of mTOR-complexes. The functional domains of the mTOR protein are depicted in the center. The binding factors present in both TORC1 and TORC2 are shown in boxes (TTT, DEPTOR, mLST8). The TORC1-specific factors are shown in ovals on top of the figure (RAPTOR, PRAS40, FKBP12-rapamycin), while the TORC2-specific factors are shown at the bottom (RICTOR, PROTOR1/2, mSIN1).

Figure 3

Upstream factors of the TOR pathway. The most important factors required for the signal integration of different stimuli by TORC1 and TORC2 are shown. Factors that enhance TOR activity are shown in squares, while those that hamper TOR activity are shown in circles. Dashed lines: effect mediated via additional proteins that are not depicted in the figure.

Figure 4

Downstream effectors of TORC1. The direct phosphorylation of targets by TORC1 has context-dependent results. Factors that interfere with the aims of TORC1 function are inactivated by phosphorylation, while supportive factors are stimulated by TORC1. Factors directly involved in transcription and translation are marked with hexagonal boxes.

Figure 5

Downstream effectors of TORC2. The direct phosphorylation of the depicted kinases by TORC2 results in their activation. Factors that interfere with the aims of TORC2 (circles, hexagon) function are inactivated by phosphorylation, while supportive factors (squares) downstream of the TORC2 are stimulated by phosphorylation.