title: Differential regulation of chemotaxis: role of Gβγ in chemokine receptor-induced cell migration.
abstract: CC and CXC chemokine receptor signalling networks are regulated in different ways. Here we show that intracellular calcium release and cell migration occur independent of Gβγ activation in response to CCL3, whereas CXCL11 induced migration of activated T-lymphocytes depends on Gβγ activation. Treatment of a range of cell types with gallein, a pharmacological inhibitor of Gβγ signalling, did not result in a reduction in CCL3 induced cellular migration, but resulted in enhanced calcium mobilisation following chemokine stimulation. Inhibition of PI3 kinase (PI3K) and AKT, which are activated downstream of Gβγ, equally had no effect on calcium release and a minor effect on cell migration. Similarly, inhibition of ERK1/2 did not prevent CCL3 induced migration. Interestingly, Gβγ as well as PI3K activation is necessary for CXCL11 induced migration of activated T-cells. These data not only confirm a role for Gβγ signalling in CXCL11 induced migration, but also demonstrate that targeting Gβγ as a therapeutic target to prevent migration in inflammatory disease may not be beneficial, at least not for CCL3 induced migration. This highlights the distinct differences in the mechanisms on how CC- and CXC-receptors activate cellular migration.
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Kerr
authors.forename: Richard O
authors.initials: RO
authors.lastname: Jacques
authors.forename: Clara
authors.initials: C
authors.lastname: Moyano Cardaba
authors.forename: Tim
authors.initials: T
authors.lastname: Tse
authors.forename: Darren
authors.initials: D
authors.lastname: Sexton
authors.forename: Anja
authors.initials: A
authors.lastname: Mueller
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D054405:Chemokine CCL3 / Q000494:pharmacology; D054371:Chemokine CXCL11 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D054405:Chemokine CCL3; D054371:Chemokine CXCL11; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D014966:Xanthenes; C007820:gallein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium