Weighing In on mTOR Complex 2 Signaling: The Expanding Role in Cell Metabolism

Abstract

In all eukaryotes, the mechanistic target of rapamycin (mTOR) signaling emerges as a master regulator of homeostasis, which integrates environmental inputs, including nutrients, energy, and growth factors, to regulate many fundamental cellular processes such as cell growth and metabolism. mTOR signaling functions through two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which correspond to two major branches of signal output. While mTORC1 is well characterized for its structure, regulation, and function in the last decade, information of mTORC2 signaling is only rapidly expanding in recent years, from structural biology, signaling network, to functional impact. Here we review the recent advances in many aspects of the mTORC2 signaling, with particular focus on its involvement in the control of cell metabolism and its physiological implications in metabolic diseases and aging.

Figure 1

The protein composition of mTORC1 and mTORC2. (a) Schematic showing main molecular components and signals sensed by mTORC1 and mTORC2 (in the rectangles) and the processes they regulate to control cell growth and survival. With high sensitivity to rapamycin, mTORC1 senses oxygen, glucose, amino acids, energy, and growth factors to regulate cell growth by inhibiting autophagy and promoting several anabolic reactions, including synthesis of protein, lipids, and nucleotides. mTORC2 is insensitive to acute rapamycin treatment but responds to growth factors and insulin to regulate lipid and glucose metabolism, as well as survival and proliferation. (b) Schematic representation of mTORC2 core components. Domains of known function or structural motifs are indicated. Description of the abbreviations listed is contained within this review.

Figure 2

The signaling network of mTORC2. (a) Schematic representation of AGC kinases downstream of mTORC2. The major positions for phosphorylation are indicated. (b) As ligands, growth factors bind to the membrane receptor, receptor tyrosine kinase (RTK), which activates PI3K to phosphorylate PIP2 to PIP3 at the plasma membrane. PTEN (phosphatase and tensin homolog) dephosphorylates PIP3 and is a key negative regulator of PI3K signaling. PIP3 or other unknown factors activate mTORC2 in distinct manners to promote the phosphorylation of conserved motifs in several AGC kinases (Akt, PKC, and SGK1). For maximal activation, Akt is phosphorylated at T308 and S473 by PDK1 and mTORC2, respectively, and subsequently promotes the activation of mTORC1, which is characterized by phosphorylation of several downstream effectors, including S6K, 4E-BP1, and ULK1. There are several other upstream regulators which can also regulate mTORC2 activity, including amino acids, ROS, ribosome, TSC complex, and GTPases, through distinct mechanisms. Description of the abbreviations listed is contained within this review.

Figure 3

mTORC2 in cell metabolism. (a) mTORC2 promotes glucose metabolism via glycolysis and PPP (pentose phosphate pathway). In response to growth factors, mTORC2 activates glucose catabolism through two main factors, Akt and c-Myc. Akt activates glycolysis at both transcriptional and posttranslational levels. c-Myc enhances the expression of genes involved in glycolysis and PPP. Activated factors are shown in red letters; suppressed factors are shown in blue. Solid line indicates direct regulation; dash line indicates indirect regulation. (b) mTORC2 promotes lipogenesis via Akt-dependent and -independent mechanisms. mTORC2 activates, via Akt, SREBP and ChREBP, two transcription factors for the expression of lipogenic genes, such as ACLY, ACC, FAS, and SCD1. mTORC2 may also stimulate lipogenesis by activating mTORC1 in an Akt-independent manner. (c) mTORC2 regulates amino acids and nucleotide metabolism. mTORC2 regulates amino acid transport by modulating activity of amino acid transporters, SLC7A5 and SLC38A2, and antiporter, xCT. In addition, mTORC2 activates glutamine transporters, SLC1A5 and SLC38A5, via c-Myc to promote glutamine uptake. By activating glycolysis, mTORC2 increases the production of 3-phospholycerate and pyruvate, which can be used to synthesize serine and alanine. mTORC2 promotes glutaminolysis via c-Myc, which transforms glutamine to glutamate and aspartate. Purine synthesis can be stimulated by mTORC2 through Akt-mediated activation of transketolase. Description of the abbreviations listed is contained within this review.

Figure 4

Impact of mTORC2-mediated metabolism on T2DM, cancer, and aging. In T2DM, the suppression of mTORC2 leads to gluconeogenesis in the liver and impaired glucose uptake in the muscle and adipose tissue, leading to insulin resistance. In pancreatic β cells, mTORC2 dysfunction also leads to reduced β-cell mass, proliferation, and impaired insulin secretion. In many types of cancers, mTORC2 activation promotes glucose uptake and glycolysis, which may contribute to the altered glucose metabolism and Warburg Effect, which fuels cell proliferation. In mammals, mTORC2 activity promotes longevity in males without established mechanism.