Heterologous regulation of chemokine receptor signaling by the lipid phosphatase SHIP in lymphocytes.
The SH2 domain-containing inositol polyphosphate 5-phosphatase (SHIP) is known to play an important role in the negative regulation by FcgammaRIIB of PI3K-dependent signaling cascades activated by the B cell antigen receptor (BCR) as well as several tyrosine-kinase coupled cytokine receptors. However, to date the role of SHIP in the regulation of PI3K-dependent signals elicited by G-protein-coupled receptors (GPCR) such as chemokine receptors has not been investigated. In this study, we report that ligation of the G-protein-coupled chemokine receptor CXCR4 by SDF-1/CXCL12 has no effect on the tyrosine phosphorylation of SHIP in the murine B cell lymphoma A20. However, co-ligation of the B cell antigen receptor and FcgammaRIIB inhibits the PI3K-dependent phosphorylation of PKB and ERK1/2 in response to CXCL12. We have also utilised a constitutively active membrane-localised SHIP mutant expressed in the Jurkat leukaemic T cell line (which do not normally express SHIP), in order to investigate the effect of this mutant on CXCL12 stimulated PI3K-dependent signaling events. Experiments have revealed that CXCL12-mediated PKB phosphorylation, chemotaxis and lipid accumulation are inhibited in the presence of this SHIP mutant. Thus, it appears that heterologous activation of SHIP by non-G-protein-coupled receptor-mediated routes can impinge on PI3K-dependent signaling pathways activated by independently ligated G-protein-coupled chemokine receptors.
Wain
Clare M
CM
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, Avon, BA2 7AY, UK.
Westwick
John
J
Ward
Stephen G
SG
D000818:Animals; D018801:CD2 Antigens / Q000235:genetics; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D002633:Chemotaxis / Q000235:genetics / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D019169:Jurkat Cells; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009154:Mutation / Q000235:genetics / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010716:Phosphatidylinositols / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology; D019707:Receptors, Chemokine / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D018801:CD2 Antigens; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D048049:Extracellular Signal-Regulated MAP Kinases; D007074:Immunoglobulin G; D019869:Phosphatidylinositol 3-Kinases; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010716:Phosphatidylinositols; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011947:Receptors, Antigen, B-Cell; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; C515255:CXCL12 protein, human; C515256:Cxcl12 protein, mouse; C445323:FCGR2A protein, human; C499173:FCGR2B protein, human; C499172:Fcgr2b protein, mouse; C118303:phosphoinositide-3,4,5-triphosphate; C034811:tetracycline resistance-encoding transposon repressor protein; C098706:INPPL1 protein, human