The Journal of Experimental Medicine
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Published online 13 September 2004 doi:10.1084/jem.20031847
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 6, 817-823
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Brief Definitive Report

 Differential Requirements for Vav Proteins in DAP10- and ITAM-mediated NK Cell Cytotoxicity

Marina Cella1, Keiko Fujikawa1,3, Ilaria Tassi1, Sunjin Kim1,2, Kevin Latinis1,2, Shinzo Nishi3, Wayne Yokoyama1,2, Marco Colonna1, and Wojciech Swat1

1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130
2 Department of Medicine and Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63130
3 Department of Biochemistry, Hokkaido University Graduate School of Medicine, 060-8638 Sapporo, Japan

Address correspondence to Wojciech Swat, Dept. of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 747-8889; Fax: (314) 362-4096; email: swat{at}pathbox.wustl.edu; or Marco Colonna. Phone: (314) 362-0367; Fax: (314) 362-4096; email: mcolonna{at}pathbox.wustl.edu

Natural killer (NK) cells express multiple activating receptors that initiate signaling cascades through DAP10- or immunoreceptor tyrosine-based activation motif–containing adapters, including DAP12 and FcR{gamma}. Among downstream signaling mediators, the guanine nucleotide exchange factor Vav1 carries out a key role in activation. However, whether Vav1 regulates only some or all NK cell–activating pathways is matter of debate. It is also possible that two other Vav family molecules, Vav2 and Vav3, are involved in NK cell activation. Here, we examine the relative contribution of each of these exchange factors to NK cell–mediated cytotoxicity using mice lacking one, two, or all three Vav proteins. We found that Vav1 deficiency is sufficient to disrupt DAP10-mediated cytotoxicity, whereas lack of Vav2 and Vav3 profoundly impairs FcR{gamma}- and DAP12-mediated cytotoxicity. Our results provide evidence that these three Vav proteins function specifically in distinct pathways that trigger NK cell cytotoxicity.

Key Words: DAP12 • NKG2D • adapters • GEF • FcR{gamma}

M. Cella and K. Fujikawa contributed equally to this work.

Abbreviations used in this paper: ADCC, antibody-dependent, cell-mediated cytotoxicity; CHO, Chinese hamster ovary; ERK, extracellular signal-regulated kinase; ITAM, immunoreceptor tyrosine-based activation motif; MEK, mitogen-activated protein kinase; nt, nucleotide; PAK1, p21-activated kinase 1; PI-3K, phosphatidylinositol-3-kinase; PLC, phospholipase C; RPA, RNase protection assay; SLP, Src homology 2 domain-containing leukocyte phosphoprotein.


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