Mechanisms of amino acid sensing in mTOR signaling pathway

Abstract

Amino acids are fundamental nutrients for protein synthesis and cell growth (increase in cell size). Recently, many compelling evidences have shown that the level of amino acids is sensed by extra- or intra-cellular amino acids sensor(s) and regulates protein synthesis/degradation. Mammalian target of rapamycin complex 1 (mTORC1) is placed in a central position in cell growth regulation and dysregulation of mTOR signaling pathway has been implicated in many serious human diseases including cancer, diabetes, and tissue hypertrophy. Although amino acids are the most potent activator of mTORC1, how amino acids activate mTOR signaling pathway is still largely unknown. This is partly because of the diversity of amino acids themselves including structure and metabolism. In this review, current proposed amino acid sensing mechanisms to regulate mTORC1 and the evidences pro/against the proposed models are discussed.

Keywords: Amino acid signaling; cell growth; mTOR; protein synthesis.

Fig. 1

Regulation of mTORC1 mTORC1 is a multiprotein complex composed of Raptor, mLST8, PRAS40, and FKBP38 and regulates protein synthesis and cell growth by phosphorylating S6K1 and 4EBP1. Rheb directly binds and activates mTOR kinase. GTP-bound active Rheb sequesters FKBP38 which otherwise binds and inhibits mTORC1. TSC1/2 heterodimer converts Rheb from GTP-bound active to GDP-bound inactive form. In Drosophila, TCTP was identified as Rheb GEF. mTORC1 activity is precisely coordinated by growth factors such as insulin or insulin-like growth factor and nutrients. Insulin binding to insulin receptor recruits IRS and subsequently activates PI3K and PDK1. PDK1 then phosphorylates and activates Akt which in turn phosphorylates two negative regulators of mTORC1, TSC2 and PRAS40, and relieves their inhibitory function. Amino acids stimulation does not phosphorylate Akt, however, strongly phosphorylates S6K and 4EBP1 in the absence of insulin stimulation. Recently three proteins, Rag, Vps34, and MAP4K3, have been presented as putative intracellular amino acid sensors. Each protein activates mTORC1 by distinctive mechanism. On the other hand, activated S6K1 phosphorylates and degrades IRS by negative feedback inhibition which in turn inhibits PI3K and mTORC1 signaling pathway (for details, see text). IRS: insulin receptor substrate; PI3K: phosphatidylinositol 3 phosphate kinase; PDK1: 3-phosphoinositide-dependent protein kinase1; Note: uncertain pathway is delineated as dashed line.

Fig. 2

Current proposed mechanisms of amino acid sensing by mTORC1 Amino acids are imported into the cells via various amino acid transporters and activate mTORC1 either by amino acid metabolites or by undefined membrane/intracellular amino acid sensor(s). Figure depicts a case of L-leucine (for details, see text). AT: aminotransferase; α-KIC: α-ketoisocaproic acid; BCKDH: branched-chain α-ketoacid dehydrogenase; GDH: glutamate dehydrogenase; AOAA: aminooxyacetic acid