Signal integration by mTORC1 coordinates nutrient input with biosynthetic output

Abstract

Flux through metabolic pathways is inherently sensitive to the levels of specific substrates and products, but cellular metabolismis also managed by integrated control mechanisms that sense the nutrient and energy status of a cell or organism. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a protein kinase complex ubiquitous to eukaryotic cells, has emerged as a critical signaling node that links nutrient sensing to the coordinated regulation of cellular metabolism. Here, the role of mTORC1 as a conduit between cellular growth conditions and the anabolic processes that promote cell growth is discussed. The emerging network of signaling pathways by which mTORC1 integrates systemic signals, in the form of secreted growth factors, with local signals, in the form of cellular nutrients (amino acids, glucose, and oxygen) and energy (ATP) is detailed. Our expanding understanding of the exquisite regulatory network upstream of mTORC1 provides molecular insights into the integrated sensing mechanisms by which diverse cellular signals converge to control cell physiology.

Regulation of global and specific mRNA translation by the mTOR signaling pathway

“…16,17 Both Raptor and Rictor serve as necessary scaffolds that contribute to the integrity of each complex and facilitate the recruitment of mTOR substrates. Whereas mTORC1 controls several anabolic processes required for cell growth and proliferation, such as protein, lipid and nucleotide synthesis, 6,18 mTORC2 regulates the activity of several AGC (protein kinase A, G and C) family members (e.g., Akt, SGK1, PKCa) that are involved in cell survival and cytoskeletal reorganization. 19 While the central role of mTOR in protein synthesis is largely attributed to mTORC1, 5,20 mounting evidence suggests that mTORC2 may play a role in cotranslational processing or maturation of nascent polypeptides as they emerge from the ribosome.…”

“…5 The latter senses and responds to nutrient availability, energy sufficiency, stress and mitogens to modulate protein synthesis. 6 In this article, we will cover the mechanisms of capdependent translation, but also discuss what is known about the role of mTOR in the translation of specific subsets of mRNAs in light of recent findings.…”

Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose

“…6,[23][24][25][26][27][28][29][30][31] Fission yeast TORC1 is activated in the presence of nitrogen and carbon sources, and phosphorylates the major S6 kinase Psk1. 22,[32][33][34] In this organism, TORC2 is also implicated in cellular nutritional responses, including the G1 arrest upon nitrogen starvation and the mitotic control in response to glucose.…”

Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory

“…mTOR exists as two distinct multiprotein complexes termed mTORC1 and mTORC2, each composed of a distinct complement of associated proteins, and differing in their cellular functions and how they are regulated. mTORC1 is rapamycin-sensitive and promotes cellular growth by increasing protein synthesis via phosphorylation of S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein (4E-BP) (Dibble and Manning 2013). In contrast, mTORC2 regulates actin polymerization and morphological changes and is insensitive to rapamycin (Cybulski and Hall 2009).…”