The endosomal sorting complex required for transport pathway mediates chemokine receptor CXCR4-promoted lysosomal degradation of the mammalian target of rapamycin antagonist DEPTOR. J Biol Chem 2015 Mar 13;290(11):6810-24
Date
01/22/2015Pubmed ID
25605718Pubmed Central ID
PMC4358107DOI
10.1074/jbc.M114.606699Scopus ID
2-s2.0-84924943410 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
G protein-coupled receptor (GPCR) signaling mediates many cellular functions, including cell survival, proliferation, and cell motility. Many of these processes are mediated by GPCR-promoted activation of Akt signaling by mammalian target of rapamycin complex 2 (mTORC2) and the phosphatidylinositol 3-kinase (PI3K)/phosphoinositide-dependent kinase 1 (PDK1) pathway. However, the molecular mechanisms by which GPCRs govern Akt activation by these kinases remain poorly understood. Here, we show that the endosomal sorting complex required for transport (ESCRT) pathway mediates Akt signaling promoted by the chemokine receptor CXCR4. Pharmacological inhibition of heterotrimeric G protein Gαi or PI3K signaling and siRNA targeting ESCRTs blocks CXCR4-promoted degradation of DEPTOR, an endogenous antagonist of mTORC2 activity. Depletion of ESCRTs by siRNA leads to increased levels of DEPTOR and attenuated CXCR4-promoted Akt activation and signaling, consistent with decreased mTORC2 activity. In addition, ESCRTs likely have a broad role in Akt signaling because ESCRT depletion also attenuates receptor tyrosine kinase-promoted Akt activation and signaling. Our data reveal a novel role for the ESCRT pathway in promoting intracellular signaling, which may begin to identify the signal transduction pathways that are important in the physiological roles of ESCRTs and Akt.
Author List
Verma R, Marchese AAuthor
Adriano Marchese PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Endosomal Sorting Complexes Required for TransportHeLa Cells
Humans
Intracellular Signaling Peptides and Proteins
Lysosomes
Mechanistic Target of Rapamycin Complex 2
Multiprotein Complexes
Phosphatidylinositol 3-Kinases
Proteolysis
Proto-Oncogene Proteins c-akt
Receptors, CXCR4
Signal Transduction
TOR Serine-Threonine Kinases
