Gene Structure, Expression Pattern, and Biological Activity of Mouse Killer Cell Activating Receptor-associated Protein (KARAP)/DAP-12

Abstract

Natural killer cell and T cell subsets express at their cell surface a repertoire of receptors for MHC class I molecules, the natural killer cell receptors (NKRs). NKRs are characterized by the existence of inhibitory and activating isoforms, which are encoded by highly homologous but separate genes present in the same locus. Inhibitory isoforms express an intracytoplasmic immunoreceptor tyrosine-based inhibition motif, whereas activating isoforms lack any immunoreceptor tyrosinebased inhibition motif but harbor a charged amino acid residue in their transmembrane domain. We previously characterized KARAP (killer cell activating receptorassociated protein), a novel disulfide-linked tyrosinephosphorylated dimer that selectively associates with the activating NKR isoforms. We report here the identification of the mouse KARAP gene, its localization on chromosome 7 and its genomic organization in five exons. Point mutation and transfection studies revealed that KARAP is a novel signaling transmembrane subunit whose transduction function depends on the integrity of an intracytoplasmic immunoreceptor tyrosinebased activation motif. In contrast to previous members of the immunoreceptor tyrosine-based activation motif polypeptide family, KARAP is ubiquitously expressed on hematopoietic and nonhematopoietic cells, suggesting its association with a broad range of activating receptors in a variety of tissues.

DAP12 Signaling Directly Augments Proproliferative Cytokine Stimulation of NK Cells during Viral Infections

“…High concentrations of proproliferative cytokines minimize the impact of Ly49H signaling through DAP12 by providing a strong stimulus to all NK cells, resulting in nonspecific, broadbased NK cell proliferation. DAP12 has previously been shown to play a crucial role in mediating NK cell cytotoxicity and cytokine production (10,11,17); however, this is the first report demonstrating that it is directly involved in mediating NK cell proliferation. We also establish that the early, nonspecific phase of MCMV-induced NK cell proliferation occurs in a DAP12-independent manner in contrast to the later phase of preferential Ly49H ϩ NK cell proliferation that is dependent on DAP12 signaling.…”

“…Mice expressing this NK cell receptor, such as C57BL/6 (B6) mice or BALB/c mice reconstituted with Ly49h by transgenesis, are significantly more resistant to MCMV infection than mice that lack Ly49H expression (3,6,7,9). Ly49H is a C-type lectin-like receptor whose expression and signaling are dependent on the ITAM-containing adaptor DAP12, also known as killer-activating receptor-associated protein or TYROBP (10,11). Ly49H specifically recognizes the MCMV-encoded protein, m157, on infected cells (12)(13)(14).…”

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

“…Generally, Ig-like receptors are subdivided into two types, namely activating and inhibitory receptors, and in some cases they are expressed on hematopoietic cells in a pair-wise manner [11][12][13][14]. Most activating receptors associate with homodimeric subunits containing ITAM, such as the FcR common g chain and KARAP/DAP12 [15,16], and deliver positive signals into the cells through interaction with their ligands [17]. For instance, the uptake of immune complexes through activating FcR for IgG augments DC maturation, leading to efficient antigen presentation [18][19][20].…”

A novel family of Ig-like receptors for HLA class I molecules that modulate function of lymphoid and myeloid cells

“…Activating NK cell receptors share a positively charged lysine residue in the transmembrane domain and a short cytoplasmic domain that lacks kinase homology or recognizable motifs for signaling mediators. Therefore, to transduce signals, these receptors associate with a separate 12-kDa protein, called DAP12 [9,[54][55][56][57][58][59], which contains a single cytoplasmic tyrosine-based activating motif (ITAM). On receptor engagement, DAP12 cytoplasmic ITAM is tyrosine phosphorylated and can bind in this form to both ZAP70 and Syk tyrosine kinases, which mediate NK cell activation.…”