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2 Integrin Regulation of RhoA in Human Neutrophils1
Division of Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden
We found that engagement of 
2 integrins on human
neutrophils induced activation of RhoA, as indicated by the increased
ratio of GTP:GTP + GDP recovered on RhoA and translocation of RhoA to a
membrane fraction. The clustering of 2 integrins also
induced a time-dependent increase in GDP bound to RhoA, which
correlated with 2 integrin-induced activation of
p190RhoGAP. The activation of p190RhoGAP was completely blocked by
[4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine]
(PP1), a selective inhibitor of Src family tyrosine kinases. However,
clustering of 2 integrins did not increase the basal
tyrosine phosphorylation of p190RhoGAP, nor did it affect the amount of
p120RasGAP bound to p190RhoGAP. Instead, the 2
integrin-induced activation of p190RhoGAP was accompanied by increased
tyrosine phosphorylation of a p190RhoGAP-associated protein,
p120RasGAP, and accumulation of both p120RasGAP and p190RhoGAP in a
membrane fraction. PP1 blocked the 2 integrin-induced
phosphorylation of p120RasGAP, as well as the translocation of
p190RhoGAP and p120RasGAP, but it did not affect the accumulation of
RhoA in the membrane fraction. In agreement with the mentioned
findings, PP1 also increased the GTP:GTP + GDP ratio recovered on RhoA
immunoprecipitated from 2 integrin-stimulated cells.
Thus, in neutrophils, 2 integrin-induced activation of
p190RhoGAP requires a signal from a Src family tyrosine kinase, but it
does not occur via the signaling pathway responsible for activation of
RhoA.
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