The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling

Abstract

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that controls a wide spectrum of cellular processes, including cell growth, differentiation, and metabolism. mTOR forms two distinct multiprotein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are characterized by the presence of raptor and rictor, respectively. mTOR controls insulin signaling by regulating several downstream components such as growth factor receptor-bound protein 10 (Grb10), insulin receptor substrate (IRS-1), F-box/WD repeat-containing protein 8 (Fbw8), and insulin like growth factor 1 receptor/insulin receptor (IGF-IR/IR). In addition, mTORC1 and mTORC2 regulate each other through a feedback loop to control cell growth. This review outlines the current understanding of mTOR regulation in insulin signaling in the context of whole body metabolism.

Keywords: insulin; mTOR complex1 (mTORC1); mTOR complex2 (mTORC2); mammalian target of rapamycin (mTOR); protein kinase B (PKB/Akt).

Figure 1

mTORC1 and mTORC2. mTOR is a serine/threonine kinase that forms two biochemically and functionally distinct complexes. mTORC1 consists of mTOR, raptor, mLST8 and the two inhibitory subunits, PRAS40 and DEPTOR, whereas mTORC2 consists of mTOR, rictor, mLST8, PRR5, SIN1 and the inhibitory subunit, DEPTOR. mTORC1 senses mitogens, oxygen levels, intracellular energy status, and amino acids to promote cell growth by regulating anabolic and catabolic processes. mTORC2 is activated by mitogen and controls cell survival, metabolism, and cytoskeletal organization. The inhibitory subunits in mTOR complexes are not presented here (PRAS40, DEPTOR). mTOR; mammalian target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; mLST8, mammalian lethal with Sec13 protein 8; PRR5, proline-rich protein 5; SIN1, stress-activated map kinase-interacting protein 1; PRAS40, proline-rich Akt substrate of 40 kDa; DEPTOR, DEP domain-containing mTOR-interacting protein.

Figure 2

Negative feedback regulation of insulin receptor substrate (IRS) by rapamycin complex 1 (mTORC1) Activated mTORC1/S6K1 inhibits IRS-1 by phosphorylating serine residues. mTOR phosphorylates mouse (m)S632 (human (h)S636), mS307 (hS312), and mS612 (hS616), and S6K1 phosphorylates mS302 (hS307), mS522 (hS527), mS265 (hS270), and mS1097 (hS1101). mTORC1 phosphorylates and stabilizes Grb10, which inhibits the interaction between IRS and the phosphorylated tyrosine of IR. Akt indirectly activates mTORC1 by phosphorylating tuberous sclerosis complex (TSC) and PRAS40. The gray images are mTORC1 targets in insulin signaling. The red line represents negative regulation. S6K1, ribosomal protein S6 kinase 1; pY, phosphotyrosine; pS, phosphoserine; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol (3,4,5)-triphosphate; PDK1, 3-phosphoinositide-dependent protein kinase 1; pT, phosphothreonine; Akt, protein kinase B (PKB); GRB10, growth factor receptor-bound protein 10; PRAS40, proline-rich AKT substrate of 40 kDa; RHEB, RAS homolog enriched in the brain.

Figure 3

The role of mTOR in insulin induced metabolic processes. The postprandial increase of insulin activates protein kinase B (PKB, also known as Akt) through PDK1and mTORC2. Akt activates mTORC1 by phosphorylating TSC1/2. Activated mTORC1 phosphorylates IRS-1, leading to negative feedback regulation of block insulin signaling. mTORC1 and mTORC2 promote lipogenesis by regulating SREBP. mTORC1 enhances lipid storage, whereas it inhibits lipolysis, β-oxidation, and ketogenesis. In addition, mTORC2 promotes glycogen synthesis and decreases gluconeogenesis. The blue line represents positive regulation, and the red line represents negative regulation. The detailed regulation is indicated in the text. PDK-1; 3-phosphoinositide-dependent protein kinase 1, SREBP; sterol regulatory element-binding protein.