Disease relevance of NCR1

• In acute myeloid leukemia (AML), leukemic blasts from approximately 80% of patients expressed very low levels of ULBPs and NCR-specific ligands [1].
• Reduced NCR expression in chronic hepatitis C was associated with a parallel decrease in NCR mediated target cell killing [2].
• This defective NCR expression in HIV-1 patients was associated with a parallel decrease of NCR-mediated killing of different tumor target cells [3].
• In the present study we show that the NK-mediated killing of two choriocarcinoma cell lines, JAR and JEG3, is induced upon engagement of natural cytotoxicity receptors (NCR) with their specific ligands [4].
• These observations suggest that 1) the NKp46 receptor participates in NK cell-mediated lysis of cells infected with an intracellular pathogen, and 2) the reduced functional capacity of NK cells is associated with severe manifestations of infectious disease [5].

High impact information on NCR1

• A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors [6].
• These findings indicate how NKp46-expressing NK cells may recognize target cells infected by influenza or parainfluenza without the decreased expression of target-cell MHC class I protein [7].
• The NK activating signal mainly involves the NKp30 natural cytotoxicity receptor, and not the NKp46 or NKp44 receptor [8].
• Two major receptors involved in human natural cytotoxicity, NKp46 and NKp44, have recently been identified [9].
• Analysis of a panel of human/hamster somatic cell hybrids revealed segregation of the NKp46 gene on human chromosome 19 [10].

Biological context of NCR1

• In gel mobility shift assay, we observed that HMG proteins 1 and 2 could bind to both negative regulatory regions (NCR1 and NCR2) [11].
• We conclude that the ligand-negative/low phenotype in AML is a consequence of cell maturation arrest on malignant transformation and that defective expression of ligands for the activating NKG2D and NCR receptors may compromise leukemia recognition by NK cells [1].
• The NKp46 gene is present and expressed in human and mouse, NKp44 is only present and expressed in human, and NKp30 is present and expressed in human but is a nonexpressed pseudogene in mouse [12].
• Again, the binding between NCR on NK cells and their putative ligands on targets leads to NK cell apoptosis [13].
• Reversibility of the NCR(dull) phenotype after CR suggested that leukemia cells might be involved in NCR down-regulation [14].

Anatomical context of NCR1

• More than 95% of peripheral blood and 85% of spleen NK cells are CD56(dim)CD16(+) and express perforin, the natural cytotoxicity receptors (NCRs) NKp30 and NKp46, as well as in part killer cell Ig-like receptors (KIRs) [15].
• Antigen presenting cells and stromal cells trigger human natural killer lymphocytes to autoreactivity: Evidence for the involvement of natural cytotoxicity receptors (NCR) and NKG2D [16].
• Antisera to NKp46 markedly inhibited lysis of infected monocytes [5].
• The NKp46 receptor contributes to NK cell lysis of mononuclear phagocytes infected with an intracellular bacterium [5].
• Increased NK activity was associated with a raise in CD3-CD56+ NK and/or CD3+CD56+ NK-like T cells, displaying enhanced expression of NKG2D and/or NKp46 receptors [17].

Associations of NCR1 with chemical compounds

• In this study, we show that the mAb-mediated engagement and clustering of one or another NCR results in the activation of an identical set of tyrosine kinases [18].
• The prolactin-mediated activation and the cortisol-mediated inhibition of natural cytotoxicity receptor (NCR) surface expression reflects gene regulation at the transcriptional level [19].
• Molecular cloning of the cDNA encoding the NKp46 molecule revealed a novel member of the immunoglobulin (Ig) superfamily, characterized by two C2-type Ig-like domains in the extracellular portion [10].
• As a consequence, l-kynurenine-treated NK cells display impaired ability to kill target cells recognized via NKp46 and NKG2D [20].
• The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function [20].

Physical interactions of NCR1

• ELISA and Far Western blotting showed that recombinant vimentin bound to a NKp46 fusion protein [21].

Regulatory relationships of NCR1

• In this study, we show that prolactin up-regulates and cortisol down-regulates the surface expression of NKp46 and NKp30 [19].
• Vimentin Expressed on Mycobacterium tuberculosis-Infected Human Monocytes Is Involved in Binding to the NKp46 Receptor [21].

Other interactions of NCR1

• To detect as-yet-unknown cell-surface molecules recognized by NCRs, we developed soluble forms of NKp30, NKp44, and NKp46 as staining reagents binding the putative cognate ligands [1].
• Treatment with differentiation-promoting myeloid growth factors, together with interferon-gamma, upregulated cell-surface levels of ULBP1 and putative NCR ligands on AML blasts, conferring an increased sensitivity to NK cell-mediated lysis [1].
• RESULTS: In patients with chronic hepatitis C, we found a significantly reduced proportion of NKp46 and NKp30 expressing NK cells compared with healthy and HBV infected subjects [2].
• Similar to other NK co-receptors, the triggering function of CD59, a glycosylphosphatidylinositol (GPI)-linked protein, depends on the simultaneous engagement of primary receptors such as NCR [22].
• We excluded the major implication of TGF-beta in NCR down-regulation [14].

Analytical, diagnostic and therapeutic context of NCR1

• Gel mobility shift assays showed that the nuclear extracts from JEG-3 cells contained proteins that form three complexes with NCR1, two with NCR2, and six with NCR3 [23].
• Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules [6].
• Our longitudinal study of AML patients showed that the NCR(dull) phenotype was acquired during leukemia development because we observed its complete (for NKp46) or partial (for NKp30) reversibility in patients achieving complete remission (CR) [14].
• In addition, RT-PCR strategy and transient transfections were used to isolate M. fascicularis NCR [24].
• These data thus show that target recognition via NKG2D or NCR triggers all aspects of NK activation, and pave the way for further dissection of the signaling pathways induced by NK cell recognition of ULBP-1 and MICA [25].

References