title: Regulation of mTORC1 by PI3K signaling.
abstract: The class I phosphoinositide 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling network directs cellular metabolism and growth. Activation of mTORC1 [composed of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8(mLST8), 40-kDa proline-rich Akt substrate (PRAS40), and DEP domain-containing mTOR-interacting protein (DEPTOR)] depends on the Ras-related GTPases (Rags) and Ras homolog enriched in brain (Rheb) GTPase 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 tuberous sclerosis complex (TSC) complex (TSC complex) [composed of TSC1, TSC2, and Tre2-Bub2-Cdc16-1 domain family member 7 (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.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Dibble
authors.affiliation: Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: lcantley@med.cornell.edu.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000201:enzymology; D003920:Diabetes Mellitus / Q000201:enzymology; D025461:Feedback, Physiological; D006801:Humans; D007328:Insulin / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008247:Lysosomes / Q000201:enzymology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases
keywords: Rag; Raptor; Rheb; TSC2; insulin; lysosome