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PMID: 26159692 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Regulation of mTORC1 by PI3K signaling.

Trends in cell biology ·Vol. 25 ·No. 9 ·2015-09-00 ·Pages 545-55

Dibble CC, Cantley LC

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.

Keywords
Rag Raptor Rheb TSC2 insulin lysosome
MeSH Terms
Animals Autistic Disorder/enzymology Diabetes Mellitus/enzymology Feedback, Physiological Humans Insulin/physiology Intracellular Signaling Peptides and Proteins/physiology Lysosomes/enzymology Mechanistic Target of Rapamycin Complex 1 Multiprotein Complexes/metabolism Phosphatidylinositol 3-Kinases/physiology Signal Transduction TOR Serine-Threonine Kinases/metabolism
Chemicals
Insulin Intracellular Signaling Peptides and Proteins Multiprotein Complexes Mechanistic Target of Rapamycin Complex 1 TOR Serine-Threonine Kinases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Dibble Christian C
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Cantley Lewis C
Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: lcantley@med.cornell.edu.
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Article Info
Journal
Trends in cell biology
Abbr.
Trends Cell Biol
ISSN
1879-3088
DOI
10.1016/j.tcb.2015.06.002
Email
lcantley@med.cornell.edu
Published
2015-09-00
Epub
2015-00-06
Pages
545-55
Language
English
Region
England
NLM ID
9200566
PMCID
PMC4734635
Subset
IM
Grants
NCI NIH HHS · K99 CA194314 · United States
NIGMS NIH HHS · R01 GM041890 · United States
NCI NIH HHS · K99-CA194314 · United States
NIGMS NIH HHS · R01-GM041890 · United States
External Links
PubMed source DOI: 10.1016/j.tcb.2015.06.002 PMC Full Text View journal details
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