Down-regulation of Rac Activity during beta 2 Integrin-mediated Adhesion of Human Neutrophils

Karim Dib, F. Melander, L. Axelsson, M.C. Dagher, P. Aspenström, T. Andersson

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Abstract

In human neutrophils, beta2 integrin engagement mediated a decrease in GTP-bound Rac1 and Rac2. Pretreatment of neutrophils with LY294002 or PP1 (inhibiting phosphatidylinositol 3-kinase (PI 3-kinase) and Src kinases, respectively) partly reversed the beta2 integrin-induced down-regulation of Rac activities. In contrast, beta2 integrins induced stimulation of Cdc42 that was independent of Src family members. The PI 3-kinase dependency of beta2 integrin-mediated decrease in GTP-bound Rac could be explained by an enhanced Rac-GAP activity, since this activity was blocked by LY204002, whereas PP1 only had a minor effect. The fact that only Rac1 but not Rac2 (the dominating Rac) redistributed to the detergent-insoluble fraction and that it was independent of GTP loading excludes the possibility that down-regulation of Rac activities was due to depletion of GTP-bound Rac from the detergent-soluble fraction. The beta2 integrin-triggered relocalization of Rac1 to the cytoskeleton was enabled by a PI 3-kinase-induced dissociation of Rac1 from LyGDI. The dissociations of Rac1 and Rac2 from LyGDI also explained the PI 3-kinase-dependent translocations of Rac GTPases to the plasma membrane. However, these accumulations of Rac in the membrane, as well as that of p47phox and p67phox, were also regulated by Src tyrosine kinases. Inasmuch as Rac GTPases are part of the NADPH oxidase and the respiratory burst is elicited in neutrophils adherent by beta2 integrins, our results indicate that activation of the NADPH oxidase does not depend on the levels of Rac-GTP but instead requires a beta2 integrin-induced targeting of the Rac GTPases as well as p47phox and p67phox to the plasma membrane.
Original languageEnglish
Pages (from-to)24181-24188
Number of pages8
JournalJournal of Biological Chemistry
Volume278(26)
Issue number26
DOIs
Publication statusPublished - 27 Jun 2003

ASJC Scopus subject areas

  • Biochemistry

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    Dib, K., Melander, F., Axelsson, L., Dagher, M. C., Aspenström, P., & Andersson, T. (2003). Down-regulation of Rac Activity during beta 2 Integrin-mediated Adhesion of Human Neutrophils. Journal of Biological Chemistry, 278(26)(26), 24181-24188. https://doi.org/10.1074/jbc.M302300200