title: The endosomal sorting complex required for transport pathway mediates chemokine receptor CXCR4-promoted lysosomal degradation of the mammalian target of rapamycin antagonist DEPTOR.
abstract: 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.
authors.affiliation: From the Biochemistry and Molecular Biology Program, and.
authors.forename: Rita
authors.initials: R
authors.lastname: Verma
authors.affiliation: From the Biochemistry and Molecular Biology Program, and Department of Molecular Pharmacology and Therapeutics, Health Sciences Division, Loyola University Chicago, Maywood, Illinois 60153 amarchese@luc.edu.
authors.forename: Adriano
authors.initials: A
authors.lastname: Marchese
mesh_terms: D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D047908:Intracellular Signaling Peptides and Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4; D058570:TOR Serine-Threonine Kinases; C556139:DEPTOR protein, human
keywords: Adrenergic Receptor; Akt PKB; CXC Chemokine Receptor Type 4 (CXCR-4); Endosomal Sorting Complexes Required for Transport (ESCRT); Epidermal Growth Factor Receptor (EGFR); G Protein-coupled Receptor (GPCR); Heterotrimeric G Protein; Insulin Receptor; Lysosome; Mammalian Target of Rapamycin (mTOR)