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

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.

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Mechanisms of amino acid sensing in mTOR signaling pathway. (2009) Eunjung Kim. Nutr Res Pract. 2009 Spring;3(1):64-71. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

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