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Activation of the Small GTPase Rap1 in Human Neutrophils

By Laura M'Rabet, P.J. Coffer, G.J.T. Zwartkruis, Barbara Franke, Anthony W. Segal, L. Koenderman and J.L. Bos

Abstract

The small GTPase Rap1 is highly expressed in human neutrophils,\ud but its function is largely unknown. Using the Rap1-\ud binding domain of RalGDS (RalGDS-RBD) as an activationspecific\ud probe for Rap1, we have investigated the regulation\ud of Rap1 activity in primary human neutrophils. We found\ud that a variety of stimuli involved in neutrophil activation,\ud including fMet-Leu-Phe (fMLP), platelet-activating factor\ud (PAF), granulocyte-macrophage colony-stimulating factor\ud (GM-CSF), and IgG-coated particles, induce a rapid and\ud transient Rap1 activation. In addition, we found that Rap1 is\ud normally activated in neutrophils from chronic granulomatous\ud disease patients that lack cytochrome b558 or p47phox\ud and have a defective NADPH oxidase system. From these\ud results we conclude that in neutrophils Rap1 is activated\ud independently of respiratory burst induction. Finally, we\ud found that Rap1 is activated by both the Ca21 ionophore\ud ionomycin and the phorbol ester 12-O-tetradecanoylphorbol\ud 13-acetate (TPA), indicating that phospholipase C (PLC)\ud activation leading to elevated levels of intracellular free Ca21\ud and diacylglycerol (DAG) can mediate Rap1 activation. However,\ud inhibition of PLC and Ca21 depletion only marginally\ud affected fMLP-induced Rap1 activation, suggesting that additional\ud pathways may control Rap1 activation

Topics: Geneeskunde
Year: 1998
OAI identifier: oai:dspace.library.uu.nl:1874/1205
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