Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 88, Issue 2, Pages 313-319Publisher
WILEY
DOI: 10.1189/jlb.0110049
Keywords
Rap1; adhesion; F-actin; polarization
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Funding
- National Heart, Lung and Blood Institute of the National Institutes of Health [P01 HL056949, P01 HL066105]
- DFG [GO1360/4-1]
- IMF Munster
- NIH [HL085100, AI076471, HL092020, GM076084]
- American Cancer Society
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Chemotaxis and integrin activation are essential processes for neutrophil transmigration in response to injury. CalDAG-GEFI plays a key role in the activation of beta 1, beta 2, and beta 3 integrins in platelets and neutrophils by exchanging a GDP for a GTP on Rap1. Here, we explored the role of CalDAG-GEFI and Rap1b in integrin-independent neutrophil chemotaxis. In a transwell assay, CalDAG-GEFI(-/-) neutrophils had a 46% reduction in transmigration compared with WT in response to a low concentration of LTB4. Visualization of migrating neutrophils in the presence of 10 mM EDTA revealed that CalDAG-GEFI(-/-) neutrophils had abnormal chemotactic behavior compared with WT neutrophils, including reduced speed and directionality. Interestingly, Rap1b(-/-) neutrophils had a similar phenotype in this assay, suggesting that CalDAG-GEFI may be acting through Rap1b. We investigated whether the deficit in integrin-independent chemotaxis in CalDAG-GEFI(-/-) neutrophils could be explained by defective cytoskeleton rearrangement. Indeed, we found that CalDAG-GEFI(-/-) neutrophils had reduced formation of F-actin pseudopodia after LTB4 stimulation, suggesting that they have a defect in polarization. Overall, our studies show that CalDAG-GEFI helps regulate neutrophil chemotaxis, independent of its established role in integrin activation, through a mechanism that involves actin cytoskeleton and cellular polarization. J. Leukoc. Biol. 88: 313-319; 2010.
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