Faculty Collaboration Database

Integrin-independent role of CalDAG-GEFI in neutrophil chemotaxis. J Leukoc Biol 2010 Aug;88(2):313-9

Date

04/24/2010

Pubmed ID

20413728

Pubmed Central ID

PMC2908939

DOI

10.1189/jlb.0110049

Scopus ID

2-s2.0-77956412592 (requires institutional sign-in at Scopus site)   28 Citations

Abstract

Chemotaxis and integrin activation are essential processes for neutrophil transmigration in response to injury. CalDAG-GEFI plays a key role in the activation of beta1, beta2, and beta3 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.

Author List

Carbo C, Duerschmied D, Goerge T, Hattori H, Sakai J, Cifuni SM, White GC 2nd, Chrzanowska-Wodnicka M, Luo HR, Wagner DD

Authors

Magdalena Chrzanowska PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Gilbert C. White MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Actins
Animals
Cell Polarity
Chemotaxis, Leukocyte
Cytoskeleton
Guanine Nucleotide Exchange Factors
Integrins
Leukotriene B4
Mice
Mice, Inbred C57BL
Neutrophils
rap1 GTP-Binding Proteins