In vitro and in vivo experimental evidence underscores the central role of NK receptor complex-ligands interactions described above in NK-mediated recognition and lysis of most tumors. However, other molecules participate in the process for which the question of whether they can fully activate or cooperate in the activation of NK cell function is still open. These are represented by NKG2D and DNAM-1, two activating molecules whose expression is not restricted to NK cells.
NKG2D (CD314) is a lectinlike homodimeric molecule that in humans recognizes MICA, MICB, and ULBPs [28-30], stress-induced molecules characterized by a domains with MHC class I folds. Whereas in mice, two NKG2D forms (mNKG2D-S and mNKG2D-S) have been characterized that associate with DAP10 and/or DAP12 [31, 32], in humans a single NKG2D exists that associates with DAP10 , a transmembrane signaling adaptor characterized by a cytoplasmic tyrosine-based YxxM motif coupling it to the PI-3K-dependent pathway. NKG2D is involved in NK-mediated killing of different tumors such as carcinoma and melanoma and T cell leukemia cell lines. On the contrary, NK-mediated killing of AML or freshly isolated neuroblastomas is NKG2D independent because these tumors are characterized by the MICA-ULBP-phenotype [13-15].
DNAM-1 (CD226) is an activating molecule that recognizes poliovirus receptor (PVR, CD155) andNectin-2 (CD112) , two closely related molecules belonging to the Nectin family, which are highly expressed by tumors of different histotype. Accordingly, DNAM-1-ligand interactions play a relevant role in NK-mediated cytotoxicity against carcinoma and melanoma cell lines, as well as ex vivo-derived neuroblastomas and myeloid (but not lymphoid) leukemic cells [13,14]. Importantly, the susceptibility to lysis of tumor cells strictly correlates with the expression and surface densities of the two lig-ands. Note that in humans, DNAM-1 is present not only on NK cells but also on T cells, monocytes, platelets, and a B cell subset. Moreover, nectins are widely expressed on normal cells including neuronal, epithelial, endothelial, and fibroblastic cells. On the basis of these observations, a DNAM-1 function has been proposed during platelet aggregation  and, through interactions with PVR on endothelium, in the diapedesis phase of leukocyte transmigration . Finally, beside the role in DNAM-1-mediated tumor cell recognition, nectins mediate homophilic and heterophilic trans-interactions that participate in the regulation of intercellular junctions  and cell-matrix adhesion. In the latter case, it has been demonstrated that stimulation of PVR inhibits cell adhesion and enhances cell motility, suggesting a role for this molecule in tumor cell biology .
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