The Journal of Experimental Medicine
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Published online 28 July 2003 doi:10.1084/jem.20021995
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© Rockefeller University Press, 0022-1007/2003/8/469 $5.00
The Journal of Experimental Medicine, Volume 198, Number 3, 469-474

Brief Definitive Report

 Vav1 Phosphorylation Is Induced by ß2 Integrin Engagement on Natural Killer Cells Upstream of Actin Cytoskeleton and Lipid Raft Reorganization

Béatrice Riteau, Domingo F. Barber and Eric O. Long

Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

Address correspondence to Eric O. Long, Laboratory of Immunogenetics, NIAID-NIH Twinbrook II, 12441 Parklawn Dr., Bethesda, MD 20852. Phone: 301-496-8266; Fax: 301-402-0259; email: elong{at}nih.gov

The guanine nucleotide exchange factor Vav1 regulates actin polymerization and contributes to cytotoxicity by natural killer (NK) cells. An open question is how Vav1 becomes activated and what receptor can signal upstream of actin cytoskeleton rearrangement upon NK cell contact with target cells. Using transfected insect cells that express ligands of human NK cell receptors, we show that engagement of the ß2 integrin LFA-1 on NK cells by intercellular adhesion molecule (ICAM)-1 led to a tyrosine phosphorylation of Vav1 that was not sensitive to cholesterol depletion and to inhibition of actin polymerization. Vav1 phosphorylation was blocked by an inhibitor of Src-family kinases, and correlated with activation of its downstream effector PAK. Binding of activation receptor 2B4 to its ligand CD48 was not sufficient for Vav1 phosphorylation. However, coengagement of 2B4 with LFA-1 resulted in an enhancement of Vav1 phosphorylation that was sensitive to cholesterol depletion and to inhibition of actin polymerization. Vav1 was recruited to a detergent-resistant membrane (DRM) fraction only when 2B4 and LFA-1 were coengaged, but not after LFA-1 engagement. Therefore, binding of LFA-1 to ICAM-1 on target cells may initiate an early signaling cascade in NK cells through activation of Vav1, leading to cytoskeleton reorganization and amplification of signals from other activation receptors.

Key Words: natural killer cell • lipid raft • LFA-1 • Vav1 • 2B4


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