Regulation of TOR by small GTPases

Abstract

TOR is a conserved serine/threonine kinase that responds to nutrients, growth factors, the bioenergetic status of the cell and cellular stress to control growth, metabolism and ageing. A diverse group of small GTPases including Rheb, Rag, Rac1, RalA and Ryh1 play a variety of roles in the regulation of TOR. For example, while Rheb binds to and activates TOR directly, Rag and Rac1 regulate its localization and RalA activates it indirectly through the production of phosphatidic acid. Here, we review recent findings on the regulation of TOR by small GTPases.

Figure 1

Regulation of small GTPases by GEFs and GAPs. A guanine nucleotide exchange factor (GEF) replaces GDP with GTP to activate the signalling function of the GTPase. Conversely, a GTPase-activating protein (GAP) stimulates hydrolysis of GTP into GDP to inactivate the small GTPase.

Figure 2

Rheb activates TORC1 both directly and indirectly. GTP-bound Rheb interacts directly with TORC1 to activate TORC1 kinase. GTP-bound Rheb also activates RalA, which activates PLD to increase production of PA. PA in turn interacts with TORC1 to stimulate TORC1 kinase activity. Rheb is inactivated by TSC1–TSC2, which acts as a GAP for Rheb. GAP, GTPase-activating protein; PA, phosphatidic acid; PLD, phospholipase D; TORC1, TOR complex 1; TSC, tuberous sclerosis complex.

Figure 3

Rag proteins mediate the activation of TORC1 in response to amino acids. The RagA/B–RagC/D heterodimer is anchored to the MP1–p14–p18 complex on the surface of the lysosome. In the absence of amino acids (left panel), RagA/B is GDP-bound whereas RagC/D is GTP-bound, and the Rag heterodimer is inactive and unable to recruit TORC1 to the lysosomal surface. In the presence of amino acids (right panel), RagA/B exchanges GDP for GTP and RagC/D converts its GTP to GDP. This Rag heterodimer acquires an active conformation that binds to and thereby recruits TORC1. Once recruited to the surface of the lysosome, TORC1 interacts with a GTP-loaded Rheb. TORC1, TOR complex 1.

Figure 4

In mammalian cells, Rac1 functions both upstream and downstream of mTOR. Once activated by TORC2, P-Rex1 (the GEF for Rac1) promotes the exchange of GDP for GTP in Rac1. Rac1 in turn interacts with and activates both mTORC1 and mTORC2 independently of its GTP loading. GEF, guanine nucleotide exchange factor; TOR, target of rapamycin; TORC1/2, target of rapamycin complex 1/2.