title: G protein-coupled chemokine receptors induce both survival and apoptotic signaling pathways.
abstract: Chemokine receptors are essential for triggering chemotaxis to immune cells; however, a number of them can also mediate death when engaged by nonchemokine ligands. When the chemokine receptor CXCR4 is engaged by stromal cell-derived factor (SDF1)alpha, it triggers cells to chemotax, and in some cell types such as neurons, causes cell death. To elucidate this dual and opposing receptor function, we have investigated whether CXCR4 activation by its chemokine SDF1alpha could lead to the simultaneous activation of both anti- and proapoptotic signaling pathways; the balance ultimately influencing cell survival. CXCR4 activation in CD4 T cells by SDF1alpha led to the activation of the prosurvival second messengers, Akt and extracellular signal-regulated protein kinase. Selective inhibition of each signal demonstrated that extracellular signal-regulated protein kinase is essential for mediating SDF1alpha-triggered chemotaxis but does not confer an antiapoptotic state. In contrast, Akt activation through CXCR4 by SDF1alpha interactions is necessary to confer resistance to apoptosis. The proapoptotic signaling pathway triggered by SDF1alpha-CXCR4 interaction involves the G(ialpha) protein-independent activation of the proapoptotic MAPK (p38). Furthermore, other chemokines and chemokine receptors also signal chemotaxis and proapoptotic effects via similar pathways. Thus, G(ialpha) protein-coupled chemokine receptors can function as death prone receptors and the balance between the above signaling pathways will ultimately mandate the fate of the activated cell.
authors.affiliation: Division of Infectious Diseases, Department of Immunology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Vlahakis
authors.forename: Angelina
authors.initials: A
authors.lastname: Villasis-Keever
authors.forename: Timothy
authors.initials: T
authors.lastname: Gomez
authors.forename: Maria
authors.initials: M
authors.lastname: Vanegas
authors.forename: Nicholas
authors.initials: N
authors.lastname: Vlahakis
authors.forename: Carlos V
authors.initials: CV
authors.lastname: Paya
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4 / Q000502:physiology*; D017154:Stromal Cells / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; C498015:GNAI2 protein, human; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go