Key factors in mTOR regulation

Abstract

Mammalian target of rapamycin (mTOR) is a protein serine/threonine kinase that controls a wide range of growth-related cellular processes. In the past several years, many factors have been identified that are involved in controlling mTOR activity. Those factors in turn are regulated by diverse signaling cascades responsive to changes in intracellular and environmental conditions. The molecular connections between mTOR and its regulators form a complex signaling network that governs cellular metabolism, growth and proliferation. In this review, we discuss some key factors in mTOR regulation and mechanisms by which these factors control mTOR activity.

Fig. 1

The signaling network that controls mTOR. mTOR exists in two distinct complexes, mTORC1 and mTORC2. The function of mTORC1 is regulated by signaling pathways responsive to amino acids sufficiency, growth factor stimulation and changes in energy levels. These pathways converge either on mTORC1 itself or on the TSC1/TSC2 complex, making up a complex signaling network. The proximal regulators of mTORC1 include Rheb and Rag small GTPases as activators and FKBP38 and PRAS40 as inhibitors. The S6K-directed phosphorylation of IRS-1 constitutes a feedback loop that downregulates the signaling activity from insulin receptors to Akt and mTOR. The mechanisms involved in mTORC2 regulation remain elusive. Arrows depict activation and T bars inhibition

Fig. 2

A schematic presentation of mTOR structures. mTOR is a large protein kinase containing multiple-functional domains. The kinase domain is located at the C-terminus and is responsible for the catalytic activity of mTORC1. The HEAT motif region located at the N-terminus and the FAT domain in the middle are involved in mediating mTOR interaction with other proteins. The FRB domain is where the FKBP12 and rapamycin complex binds, which is within the region that binds to FKBP38. mTOR is also phosphorylated by several kinases, including itself

Fig. 3

Two mTOR complexes and their functions. mTORC1 is composed of mTOR, mLST8, raptor and PRAS40. Its function is involved many growth-related processes and oxygen adaptation and is sensitive to rapamycin. mTORC2 shares mTOR and mLST8 with mTORC1, but contains a few other unique components, including rictor, mSIN1 and PRR5

Fig. 4

A model for the role of FKBP38 in mTORC1 regulation. FKBP38 inhibits mTOR activity through direct binding to mTOR. In GTP-bound form, Rheb interacts with FKBP38 and liberates mTORC1 for activation. The action of Rheb is terminated by the TSC1/TSC2 complex, which promotes the hydrolysis of bounded GTP to GDP. Reloading of Rheb with GTP by a putative guanine exchange factor repeats the cycle

Fig. 5

A model for the role of the Rag GTPases in mTORC1 regulation. In cells starved for amino acids, mTORC1 resides on membrane structures distributed throughout the cytoplasm. Re-stimulation with amino acids activates the heterodimers of the Rag small GTPases, which causes mTORC1 redistribution to Rab7-enriched endosomal compartments, where it is activated by Rheb