DAP10 is only associated with one activating receptor, which is NKG2D. Human NKG2D only associates with homodimers of DAP10, and murine NK cells possess a similar version, NKG2D-L, which also associates only with DAP10 dimers [50,65,140]. Murine NK cells, however, also express a shorter version, NKG2D-S, which lacks 13 amino-terminal amino acids in the cytoplasmic domain and can uniquely associate with homodimers of both DAP10 and DAP12 [50,65,140]. In contrast to ITAM-signaling receptors, the previously mentioned YINM motif on DAP10 becomes phosphorylated on ligation of NKG2D , thereby establishing a membrane-proximal binding site for SH2 domains of the Grb2 adaptor and the p85 subunit of PI3K [35, 180]. Grb2 and PI3K recruitment are also part of the ITAM-initiated activating pathway, and it has been shown that DAP10 signaling plays a costimulatory role that amplifies ITAM signaling [65, 69,141,178]. Similar costimulatory functions by CD28 and CD19 that enhance antigen receptor signaling in T- and B-cells, respectively, are also thought to be derived mainly from recruitment of PI3K [4,30]. Numerous reports, however, indicate that NKG2D/DAP10 can also directly stimulate cytotoxicity [6,16,75,196]. One ofthese studies even utilized NK cells from mice lacking Syk, ZAP-70, and DAP12 .
Significant differences have emerged that distinguish DAP10-initiated signals from those downstream of ITAMs. First, Billadeau et al. have shown in human NK cells that DAP10 signaling through the YINM motif is independent of Syk but involves Src kinases, SLP-76, PLCy, Vav-1, and Rho family GTPases, whereas ITAM signaling involves all of these, including Syk . Their evidence also indicates that DAP10-mediated phosphorylation ofPLCy and Vav requires the YINM tyrosine, but is independent of PI3K . This suggests important roles for other effector proteins that might be recruited to the phosphorylated YINM. In line with this possibility, one study has found that NKG2D ligation stimulates Janus kinase 2 (Jak2) and STAT5, which are not characteristic effectors in ITAM signaling . Several reports indicate that DAP10 can stimulate cytotoxicity, but not IFNy production by NK cells, whereas DAP12 can trigger both responses [50,69,178,196]. Although the basis of this is not entirely clear, the activation of Syk/ZAP-70 through ITAMs, which represents a major distinction from DAP10 signaling, maybe critical for the cytokine response . Second, evidence has been provided that NKG2D/DAP10-mediated activation is apparently less sensitive to attenuation by MHC class I-binding inhibitory receptors, such as KIR, whereas ITAM-containing receptor signaling is readily blocked by these inhibitory receptors [10,32,44,49]. The molecular basis for this insensitivity to inhibition is currently unclear, but it allows NK cells to attack tumors that upregulate NKG2D ligands yet still express MHC-I. A third difference in downstream signaling is the activation of different Vav subtypes by ITAM- and YINM-coupled receptors . These differences in Vav activation will be detailed in the next section.
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