Nitric oxide produced in response to engagement of beta 2 integrins on human neutrophils activates the monomeric GTPases Rap1 and Rap2 and promotes adhesion

Veronika Jenei, Ravi Kiran Deevi, Catherine Anne Adams, Lena Axelsson, David Graham Hirst, Tommy Andersson, Karim Dib

Research output: Contribution to journalArticlepeer-review

24 Citations (SciVal)

Abstract

We found that engagement of beta 2 integrins on human neutrophils increased the levels of GTP-bound Rap1 and Rap2. Also, the activation of Rap1 was blocked by PP1, SU6656, LY294002, GF109203X, or BAPTA-AM, which indicates that the downstream signaling events in Rap1 activation involve Src tyrosine kinases, phosphoinositide 3-kinase, protein kinase C, and release of calcium. Surprisingly, the beta 2 integrin-induced activation of Rap2 was not regulated by any of the signaling pathways mentioned above. However, we identified nitric oxide as the signaling molecule involved in beta 2 integrin-induced activation of Rap1 and Rap2. This was illustrated by the fact that engagement of beta 2 integrins increased the production of nitrite, a stable end-product of nitric oxide. Furthermore, pretreatment of neutrophils with N-omega-mono-methy1-L-arginine, or 1400W, which are inhibitors of inducible nitric- oxide synthase, blocked beta 2 integrin-induced activation of Rap1 and Rap2. Similarly, R-P-8pCPT-cGMPS, an inhibitor of cGMP-dependent serine/threonine kinases, also blunted the beta 2 integrin-induced activation of Rap GTPases. Also nitric oxide production and its downstream activation of cGMP-dependent serine/threonine kinases were essential for proper neutrophil adhesion by beta 2 integrins. Thus, we made the novel findings that beta 2 integrin engagement on human neutrophils triggers production of nitric oxide and its downstream signaling is essential for activation of Rap GTPases and neutrophil adhesion.
Original languageEnglish
Pages (from-to)35008-35020
JournalJournal of Biological Chemistry
Volume281
Issue number46
DOIs
Publication statusPublished - 2006

Subject classification (UKÄ)

  • Cancer and Oncology

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