Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 200, Issue 6, Pages 817-823Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20031847
Keywords
DAP12; NKG2D; adapters; GEF; FcR gamma
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Funding
- NIAID NIH HHS [R01 AI056139, 5R01AI056139-03] Funding Source: Medline
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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 FcRgamma- and DAP12-mediated cytotoxicity. Our results provide evidence that these three Vav proteins function specifically in distinct pathways that trigger NK cell cytotoxicity.
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