Amino acid regulation of TOR complex 1

Abstract

TOR complex 1 (TORC1), an oligomer of the mTOR (mammalian target of rapamycin) protein kinase, its substrate binding subunit raptor, and the polypeptide Lst8/GbetaL, controls cell growth in all eukaryotes in response to nutrient availability and in metazoans to insulin and growth factors, energy status, and stress conditions. This review focuses on the biochemical mechanisms that regulate mTORC1 kinase activity, with special emphasis on mTORC1 regulation by amino acids. The dominant positive regulator of mTORC1 is the GTP-charged form of the ras-like GTPase Rheb. Insulin, growth factors, and a variety of cellular stressors regulate mTORC1 by controlling Rheb GTP charging through modulating the activity of the tuberous sclerosis complex, the Rheb GTPase activating protein. In contrast, amino acids, especially leucine, regulate mTORC1 by controlling the ability of Rheb-GTP to activate mTORC1. Rheb binds directly to mTOR, an interaction that appears to be essential for mTORC1 activation. In addition, Rheb-GTP stimulates phospholipase D1 to generate phosphatidic acid, a positive effector of mTORC1 activation, and binds to the mTOR inhibitor FKBP38, to displace it from mTOR. The contribution of Rheb's regulation of PL-D1 and FKBP38 to mTORC1 activation, relative to Rheb's direct binding to mTOR, remains to be fully defined. The rag GTPases, functioning as obligatory heterodimers, are also required for amino acid regulation of mTORC1. As with amino acid deficiency, however, the inhibitory effect of rag depletion on mTORC1 can be overcome by Rheb overexpression, whereas Rheb depletion obviates rag's ability to activate mTORC1. The rag heterodimer interacts directly with mTORC1 and may direct mTORC1 to the Rheb-containing vesicular compartment in response to amino acid sufficiency, enabling Rheb-GTP activation of mTORC1. The type III phosphatidylinositol kinase also participates in amino acid-dependent mTORC1 activation, although the site of action of its product, 3'OH-phosphatidylinositol, in this process is unclear.

Fig. 1.

Candidate mechanisms for Rheb-GTP activation of mammalian target of rapamycin complex 1 (mTORC1). The segment of mTOR from ∼AA 1967-2500 is pictured; cleft in rectangle divides the catalytic domain into upper (AA 2147-2300) and lower (AA 2301-2430) lobes. Loop represents the FKBP12-rapamycin binding (FRB) domain (AA 2014-2115). Insulin and growth factors promote Rheb GTP charging by inhibition of the tuberous sclerosis complex (TSC), a Rheb GTPase activator, as illustrated in C. Three models for mTORC1 activation by Rheb-GTP are illustrated. A: Rheb binds to the upper lobe of the catalytic domain and when GTP charged, enables mTOR activation. Amino acid withdrawal, through an effect on the lower lobe, interferes with Rheb binding to the upper lobe. B: ability of Rheb-GTP to promote activation of phospholipase D1 generates phosphatidic acid (PA), which binds to the FRB domain, promoting activation. C: Rheb-GTP binds to mTOR inhibitor FKBP38, competing with and displacing it from mTOR, disinhibiting the mTOR kinase activity. Site of action of amino acids in B and C is unknown.

Fig. 2.

Possible mechanism of action of the rag GTPases in amino acid regulation of mTORC1. The rag GTPases exist as an obligatory heterodimer. GTP charging of the rag A/B partner, possibly dependent on amino acid sufficiency, promotes association of the rag heterodimer with mTORC1 and its translocation to a membrane compartment enriched in Rheb, thereby enabling mTORC1 activation when Rheb is GTP charged. Based on data in Refs. and 93; see text for details.