Phosphatidic acid-mediated regulation of neutrophil plasma membrane CD45-phosphotyrosine phosphatase.
CD45-phosphotyrosine phosphatase (PTPase) constitutes the major portion of thr PTPase activity within plasma membranes of neutrophilic leukocytes, where it regulates signals leading to functional activation. We have previously demonstrated that the catalytic component of neutrophil plasma membrane CD45-PTPASE is regulated by a cytosolic inactivator which itself is attenuated upon cellular stimulation, allowing enzyme translocated from granule stores to express full activity. The present study investigated mechanisms of cytosolic inactivator attenuation. Preincubation of plasma membranes of stimulated neutrophils with cytosol from resting cells resulted in a rapid loss of membrane-associated PTPase activity. Phosphatidic acid had no direct effect on plasma membrane PTPase activity but blunted in a dose dependent manner the effects of the PTPase inactivator. Inactivator attenuation was not observed with equivalent concentrations of either diacylglycerol or lysophosphatidic acid. Optimal attenuation of inactivator activity was obtained with long chain, soluble ligands, such as dicapryl phosphatidic acid. Inhibitors of neutrophil plasma membrane ecto-phosphatidic acid phosphohydrolase did not block inactivator attenuation, suggesting that phosphatidic acid and not one of its metabolites was the entity responsible. In conclusion, neutrophil plasma membrane PTPase is dynamically regulated by a cytosolic inactivator, the inhibition of which may potentiate the effects of PTPase translocated during cellular stimulation. Phosphatidic acid generated as a consequence of cellular stimulation may mediate this inhibition and thereby regulate the effects of tyrosine kinases activated during the initial phases of cell stimulation.
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Bone Marrow Transplantation Laboratory, Methodist Hospital of Indiana, Indianapolis, USA.
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D002462:Cell Membrane / Q000201:enzymology; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors; D006801:Humans; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D010712:Phosphatidic Acids / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D010712:Phosphatidic Acids; D017027:Protein Tyrosine Phosphatases