Activation of SHIP by NADPH oxidase-stimulated Lyn leads to enhanced apoptosis in neutrophils.
Neutrophils undergo rapid spontaneous apoptosis. Multiple antiapoptotic stimuli can inhibit this process via activation of the Akt pathway. However, despite no such effect singly, combined anti- and proapoptotic stimuli inhibit Akt activity, leaving the cells susceptible to accelerated apoptosis. The blockade of Akt activation depended on reduced phosphoinositide 3,4,5-trisphosphate levels but not decreased phosphatidylinositol 3-kinase activity, thus implicating the involvement of an inositol phosphatase. Evidence for SHIP involvement was provided by SHIP localization to membrane receptors and subsequent activation along with the observed inability of SHIP -/- neutrophils to exhibit enhanced apoptosis with the stimulus combination. Activation of SHIP was found to depend on Lyn activation, and this, in turn, required NADPH oxidase. Neutrophils from chronic granulomatous disease patients and Lyn -/- mice no longer responded to the combined stimuli. Thus, we propose a role for oxidants and Lyn in SHIP regulation and suggest a novel mechanism for regulating neutrophil apoptosis.
Gardai
Shyra
S
Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Whitlock
Ben B
BB
Helgason
Cheryl
C
Ambruso
Dan
D
Fadok
Valerie
V
Bratton
Donna
D
Henson
Peter M
PM
D017209:Apoptosis; D015153:Blotting, Western; D004789:Enzyme Activation; D006105:Granulomatous Disease, Chronic / Q000097:blood; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D050356:Lipid Metabolism; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
D007295:Inositol Phosphates; C118500:inositol 3,4,5-trisphosphate; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010100:Oxygen