Regulation of mTORC1 by PI3K Signaling

By Christian C. Dibble, Lewis C. Cantley. Trends in Cell Biology, 2015

751 citations recorded by the source corpus.

The class I phosphoinositide 3-kinase (PI3K) - mechanistic target of rapamycin complex 1 (mTORC1) signaling network directs cellular metabolism and growth. Activation of mTORC1, which is composed of mTOR, Raptor, mLST8, PRAS40, and DEPTOR, depends on the Rag and Rheb GTPases, and requires signals from amino acids, glucose, oxygen, energy (ATP), and growth factors (including cytokines and hormones such as insulin). Here we discuss the signal transduction mechanisms through which growth factor-responsive PI3K signaling activates mTORC1. We focus on how PI3K-dependent activation of Akt and spatial regulation of the TSC complex (composed of TSC1, TSC2, and TBC1D7) switches on Rheb at the lysosome, where mTORC1 is activated. Integration of PI3K- and amino acid-dependent signals upstream of mTORC1 at the lysosome is detailed in a working model. A coherent understanding of the PI3K-mTORC1 network is imperative as its dysregulation has been implicated in diverse pathologies including cancer, diabetes, autism, and aging.

Subfields: Immunology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/57b3c45c5546a74e4591be8bc4df1079671b360f

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Citations in the corpus

Nutrient sensing and TOR signaling in yeast and mammals (2017, positive): “Growth factors stimulate lysosomal RHEB through the PI3K-PDK1-AKT pathway (reviewed in Pearce et al , 2010; Dibble & Cantley, 2015).”
Branched Chain Amino Acids: Beyond Nutrition Metabolism (2018, background): “The process of proliferation and growth of cancer cells need to acquire essential nutrients from the tumor microenvironment [108].”
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways (2017, background): “Phosphorylation at the tail domain residue S473 is mediated by mTORC2, through a little understood process that involves PI3K activity [223,249].”
The PI3K pathway in human disease (2017, positive): “The activation of S6K1/2 and inhibition of 4EBP1 by mTORC1 (Figure 2) drives anabolic processes, including protein and nucleotide synthesis as well as transcriptional activation of genes encoding enzymes of glycolysis and the pentose phosphate pathway (Dibble and Cantley, 2015).”
A systems study reveals concurrent activation of AMPK and mTOR by amino acids (2016, background): “22).”