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J. Biol. Chem., Vol. 281, Issue 46, 35008-35020, November 17, 2006

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Nitric Oxide Produced in Response to Engagement of 2 Integrins on Human Neutrophils Activates the Monomeric GTPases Rap1 and Rap2 and Promotes Adhesion^*

Veronika Jenei¹², Ravi Kiran Deevi², Catherine Anne Adams^¶, Lena Axelsson, David Graham Hirst^¶, Tommy Andersson, and Karim Dib³

From the Department of Laboratory Medicine, Division of Experimental Pathology, Lund University, Malmö University Hospital, SE-20502 Malmö, Sweden, the Centre for Cancer Research and Cell Biology, Division of Infection and Immunity, Queen's University Belfast, Whitla Medical Building, Immunology Section, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom, and the ^¶School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom

We found that engagement of 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 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 2 integrin-induced activation of Rap1 and Rap2. This was illustrated by the fact that engagement of 2 integrins increased the production of nitrite, a stable end-product of nitric oxide. Furthermore, pretreatment of neutrophils with N-monomethyl-L-arginine, or 1400W, which are inhibitors of inducible nitric-oxide synthase, blocked 2 integrin-induced activation of Rap1 and Rap2. Similarly, R_p-8pCPT-cGMPS, an inhibitor of cGMP-dependent serine/threonine kinases, also blunted the 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 2 integrins. Thus, we made the novel findings that 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.

Received for publication, February 10, 2006 , and in revised form, August 28, 2006.

^* This work was supported in part by grants from the Swedish Cancer Foundation and the Swedish Medical Research Council (to T. A.); by the Crafoord Foundation, the Johan and Greta Kocks Foundation, and the Royal Physiographic Society in Lund (to K. D.); and by the Österlund Foundation, the Universitetssjukhust-Malmö Almänna Sjukhus Research Foundations, and the Blood and Defense Network of Lund University (to T. A. and K. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Involved in an exchange program between the Swedish Institute, and the Hungarian Academy of Sciences, and partly supported by the Swedish Institute; the European Union (project of the European Union for Centre of Excellence in Biomolecular Chemistry, QLK2-CT-2002–90436); and the Faculty of Medicine and Health Sciences, Queen's University Belfast (Friar funds).

² Both authors contributed equally to this work.

³ Supported by the Faculty of Medicine and Health Sciences, Queen's University Belfast. To whom correspondence should be addressed. Tel.: 44-28-90-27-26-34; Fax: 44-28-90-32-58-39; E-mail: k.dib{at}qub.ac.uk.

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