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

Jenei, Veronika; Deevi, Ravi Kiran; Adams, Catherine Anne; Axelsson, Lena LU ; Hirst, David Graham; Andersson, Tommy LU and Dib, Karim LU (2006) In Journal of Biological Chemistry 281(46). p.35008-35020
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
281
issue
46
pages
35008 - 35020
publisher
ASBMB
external identifiers
  • wos:000241933700034
  • scopus:33845921866
ISSN
1083-351X
DOI
10.1074/jbc.M601335200
language
English
LU publication?
yes
id
f6984b83-a6e2-4f20-8957-1ef48f1a0f79 (old id 377026)
date added to LUP
2007-10-05 14:34:39
date last changed
2019-04-10 01:41:54
@article{f6984b83-a6e2-4f20-8957-1ef48f1a0f79,
  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.},
  author       = {Jenei, Veronika and Deevi, Ravi Kiran and Adams, Catherine Anne and Axelsson, Lena and Hirst, David Graham and Andersson, Tommy and Dib, Karim},
  issn         = {1083-351X},
  language     = {eng},
  number       = {46},
  pages        = {35008--35020},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Nitric oxide produced in response to engagement of beta 2 integrins on human neutrophils activates the monomeric GTPases Rap1 and Rap2 and promotes adhesion},
  url          = {http://dx.doi.org/10.1074/jbc.M601335200},
  volume       = {281},
  year         = {2006},
}