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Gene Review

KLRK1  -  killer cell lectin-like receptor subfamily...

Homo sapiens

Synonyms: CD314, D12S2489E, KLR, Killer cell lectin-like receptor subfamily K member 1, NK cell receptor D, ...
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Disease relevance of KLRK1


High impact information on KLRK1


Chemical compound and disease context of KLRK1


Biological context of KLRK1


Anatomical context of KLRK1


Associations of KLRK1 with chemical compounds

  • Recently, using soluble recombinant molecules, the HCMV UL16 glycoprotein was shown to interact with some ligands of the activating immunoreceptor NKG2D and, therefore, may also function as a viral immunomodulator [9].
  • Transcriptional Regulation of ULBP1, a Human Ligand of the NKG2D Receptor [21].
  • Here, the crystal structure of free human NKG2D and in silico and in vitro alanine-scanning mutagenesis analyses of the complex interfaces indicate that NKG2D recognition degeneracy is not explained by a classical induced-fit mechanism [22].
  • Unlike other NKG2D ligands, Letal mRNA expression progressively decreased after treatment of tumor cells with retinoic acid [23].
  • Poly (I:C) challenge 1) activated nuclear factor-kappaB (NF-kappaB), 2) increased IL-8 release, and 3) up-regulated NKG2D ligands and NK-cell-mediated lysis of muscle cells [24].

Physical interactions of KLRK1

  • This study was designed to evaluate whether HIV-1 could interfere with the expression of NK cell-activating ligands, specifically the human leukocyte antigen (HLA)-I-like MICA and ULBP molecules that bind NKG2D, an activating receptor expressed by all NK cells [5].
  • The ligands for NKG2D are the major histocompatibility complex class I-related chain (MIC)A and MICB glycoproteins, and the UL-16-binding proteins (ULBPs) [25].
  • NKG2D binds diagonally across the ULBP3 alpha helices, creating a complementary interface, an asymmetrical subunit orientation, and local conformational adjustments in the receptor [26].
  • Human ULBP1 and ULBP2 interact with the NKG2D receptor to activate effector cells in the immune system [27].
  • The NKG2D receptor costimulates effector/memory CD8 T cells and is normally absent on CD4 T cells but can be induced by T cell antigen receptor complex stimulation and interleukin-15 (IL-15) [28].

Co-localisations of KLRK1


Regulatory relationships of KLRK1

  • Furthermore, CD34+ hematopoietic progenitors undergoing granulomonocytic differentiation expressed NKG2D ligands [30].
  • Proteolytic shedding of both NKG2D ligands MICA and ULBP2 by tumor cells was strongly enhanced after phorbol 12-myristate 13-acetate treatment and paralleled by a markedly reduced susceptibility to NKG2D-mediated cytotoxicity [31].
  • In this study, we show that transforming growth factor beta1 (TGFbeta1) down-regulates the surface expression of NKp30 and in part of NKG2D but not that of other triggering receptors such as NKp46 [32].
  • Placenta-derived soluble MHC class I chain-related molecules down-regulate NKG2D receptor on peripheral blood mononuclear cells during human pregnancy: a possible novel immune escape mechanism for fetal survival [33].
  • In this regard, the NKG2D molecule first identified on NK cells and classified as an activating NK cell receptor is also an important receptor for CD8(+) T cells [34].

Other interactions of KLRK1

  • Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D [35].
  • Taken together, our data suggest that impaired NK function in cancer patients can be attributed to down-modulation of activating receptors, such as NKG2D, via secretion of TGF-beta1 [3].
  • Freshly isolated NK cells are NKp44 negative and lysed pEC exclusively in an NKG2D-dependent fashion [36].
  • Both proteins bound the activating receptor NKG2D, and RAET1G bound the human CMV protein UL16 [35].
  • This KLR is commonly expressed by human NK cells as well as TCRgammadelta(+) and TCRalphabeta(+)CD8(+) T lymphocytes, but it has been also detected in CD4(+) T cells from rheumatoid arthritis and cancer patients [4].

Analytical, diagnostic and therapeutic context of KLRK1

  • In conclusion, strategies aimed to inhibit interactions between NKp44 and NKG2D on human NK cells and so far unknown ligands on pEC may prevent direct NK responses against xenografts but not xenogeneic Ab-dependent cell-mediated cytotoxicity [36].
  • Furthermore, flow cytometry revealed that IL-15 increased expression of the activation receptor NKG2D on NK cells, particularly among the CD16Hi cytolytically active cells [20].
  • We have developed a quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) assay designed to determine specific and absolute mRNA levels for NKG2-A/B, -C, -E, -F, -H and NKG2-D [37].
  • Effector cells from all these subsets could be stimulated by ligation of NKG2D [38].
  • NKG2D is an important immunosurveillance receptor that responds to stress-induced ligand expression on tumors and virus-infected cells [39].


  1. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Carbone, E., Neri, P., Mesuraca, M., Fulciniti, M.T., Otsuki, T., Pende, D., Groh, V., Spies, T., Pollio, G., Cosman, D., Catalano, L., Tassone, P., Rotoli, B., Venuta, S. Blood (2005) [Pubmed]
  2. Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Pende, D., Rivera, P., Marcenaro, S., Chang, C.C., Biassoni, R., Conte, R., Kubin, M., Cosman, D., Ferrone, S., Moretta, L., Moretta, A. Cancer Res. (2002) [Pubmed]
  3. Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. Lee, J.C., Lee, K.M., Kim, D.W., Heo, D.S. J. Immunol. (2004) [Pubmed]
  4. Expression and function of NKG2D in CD4(+) T cells specific for human cytomegalovirus. S??ez-Border??as, A., Gum??, M., Angulo, A., Bellosillo, B., Pende, D., L??pez-Botet, M. Eur. J. Immunol. (2006) [Pubmed]
  5. Human immunodeficiency virus 1 Nef protein downmodulates the ligands of the activating receptor NKG2D and inhibits natural killer cell-mediated cytotoxicity. Cerboni, C., Neri, F., Casartelli, N., Zingoni, A., Cosman, D., Rossi, P., Santoni, A., Doria, M. J. Gen. Virol. (2007) [Pubmed]
  6. NKG2D-mediated antitumor activity by tumor-infiltrating lymphocytes and antigen-specific T-cell clones isolated from melanoma patients. Maccalli, C., Nonaka, D., Piris, A., Pende, D., Rivoltini, L., Castelli, C., Parmiani, G. Clin. Cancer Res. (2007) [Pubmed]
  7. NKG2D ligand expression in human colorectal cancer reveals associations with prognosis and evidence for immunoediting. McGilvray, R.W., Eagle, R.A., Watson, N.F., Al-Attar, A., Ball, G., Jafferji, I., Trowsdale, J., Durrant, L.G. Clin. Cancer Res. (2009) [Pubmed]
  8. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Groh, V., Wu, J., Yee, C., Spies, T. Nature (2002) [Pubmed]
  9. Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein. Welte, S.A., Sinzger, C., Lutz, S.Z., Singh-Jasuja, H., Sampaio, K.L., Eknigk, U., Rammensee, H.G., Steinle, A. Eur. J. Immunol. (2003) [Pubmed]
  10. Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Armeanu, S., Bitzer, M., Lauer, U.M., Venturelli, S., Pathil, A., Krusch, M., Kaiser, S., Jobst, J., Smirnow, I., Wagner, A., Steinle, A., Salih, H.R. Cancer Res. (2005) [Pubmed]
  11. MICA expressed by multiple myeloma and monoclonal gammopathy of undetermined significance plasma cells Costimulates pamidronate-activated gammadelta lymphocytes. Girlanda, S., Fortis, C., Belloni, D., Ferrero, E., Ticozzi, P., Sciorati, C., Tresoldi, M., Vicari, A., Spies, T., Groh, V., Caligaris-Cappio, F., Ferrarini, M. Cancer Res. (2005) [Pubmed]
  12. BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia. Boissel, N., Rea, D., Tieng, V., Dulphy, N., Brun, M., Cayuela, J.M., Rousselot, P., Tamouza, R., Le Bouteiller, P., Mahon, F.X., Steinle, A., Charron, D., Dombret, H., Toubert, A. J. Immunol. (2006) [Pubmed]
  13. Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias. Nowbakht, P., Ionescu, M.C., Rohner, A., Kalberer, C.P., Rossy, E., Mori, L., Cosman, D., De Libero, G., Wodnar-Filipowicz, A. Blood (2005) [Pubmed]
  14. Human cytomegalovirus-encoded UL16 discriminates MIC molecules by their alpha2 domains. Spreu, J., Stehle, T., Steinle, A. J. Immunol. (2006) [Pubmed]
  15. The genomic organization of NKG2C, E, F, and D receptor genes in the human natural killer gene complex. Glienke, J., Sobanov, Y., Brostjan, C., Steffens, C., Nguyen, C., Lehrach, H., Hofer, E., Francis, F. Immunogenetics (1998) [Pubmed]
  16. Cell surface organization of stress-inducible proteins ULBP and MICA that stimulate human NK cells and T cells via NKG2D. Eleme, K., Taner, S.B., Onfelt, B., Collinson, L.M., McCann, F.E., Chalupny, N.J., Cosman, D., Hopkins, C., Magee, A.I., Davis, D.M. J. Exp. Med. (2004) [Pubmed]
  17. ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15. Sutherland, C.L., Rabinovich, B., Chalupny, N.J., Brawand, P., Miller, R., Cosman, D. Blood (2006) [Pubmed]
  18. Interaction between human NK cells and bone marrow stromal cells induces NK cell triggering: role of NKp30 and NKG2D receptors. Poggi, A., Prevosto, C., Massaro, A.M., Negrini, S., Urbani, S., Pierri, I., Saccardi, R., Gobbi, M., Zocchi, M.R. J. Immunol. (2005) [Pubmed]
  19. Role of NK cell-activating receptors and their ligands in the lysis of mononuclear phagocytes infected with an intracellular bacterium. Vankayalapati, R., Garg, A., Porgador, A., Griffith, D.E., Klucar, P., Safi, H., Girard, W.M., Cosman, D., Spies, T., Barnes, P.F. J. Immunol. (2005) [Pubmed]
  20. Interleukin-15 activates human natural killer cells to clear the intestinal protozoan cryptosporidium. Dann, S.M., Wang, H.C., Gambarin, K.J., Actor, J.K., Robinson, P., Lewis, D.E., Caillat-Zucman, S., White, A.C. J. Infect. Dis. (2005) [Pubmed]
  21. Transcriptional Regulation of ULBP1, a Human Ligand of the NKG2D Receptor. L??pez-Soto, A., Qui??ones-Lombra??a, A., L??pez-Arbes??, R., L??pez-Larrea, C., Gonz??lez, S. J. Biol. Chem. (2006) [Pubmed]
  22. Symmetry recognizing asymmetry: analysis of the interactions between the C-type lectin-like immunoreceptor NKG2D and MHC class I-like ligands. McFarland, B.J., Kortemme, T., Yu, S.F., Baker, D., Strong, R.K. Structure (Camb.) (2003) [Pubmed]
  23. Letal, A tumor-associated NKG2D immunoreceptor ligand, induces activation and expansion of effector immune cells. Conejo-Garcia, J.R., Benencia, F., Courreges, M.C., Khang, E., Zhang, L., Mohamed-Hadley, A., Vinocur, J.M., Buckanovich, R.J., Thompson, C.B., Levine, B., Coukos, G. Cancer Biol. Ther. (2003) [Pubmed]
  24. Expression of toll-like receptors by human muscle cells in vitro and in vivo: TLR3 is highly expressed in inflammatory and HIV myopathies, mediates IL-8 release and up-regulation of NKG2D-ligands. Schreiner, B., Voss, J., Wischhusen, J., Dombrowski, Y., Steinle, A., Lochmüller, H., Dalakas, M., Melms, A., Wiendl, H. FASEB J. (2006) [Pubmed]
  25. Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. Raffaghello, L., Prigione, I., Airoldi, I., Camoriano, M., Levreri, I., Gambini, C., Pende, D., Steinle, A., Ferrone, S., Pistoia, V. Neoplasia (2004) [Pubmed]
  26. Conformational plasticity revealed by the cocrystal structure of NKG2D and its class I MHC-like ligand ULBP3. Radaev, S., Rostro, B., Brooks, A.G., Colonna, M., Sun, P.D. Immunity (2001) [Pubmed]
  27. Genomic organization and evolution of the ULBP genes in cattle. Larson, J.H., Marron, B.M., Beever, J.E., Roe, B.A., Lewin, H.A. BMC Genomics (2006) [Pubmed]
  28. Immunostimulation by induced expression of NKG2D and its MIC ligands in HTLV-1-associated neurologic disease. Azimi, N., Jacobson, S., Tanaka, Y., Corey, L., Groh, V., Spies, T. Immunogenetics (2006) [Pubmed]
  29. NKG2D-mediated cytotoxicity toward oligodendrocytes suggests a mechanism for tissue injury in multiple sclerosis. Saikali, P., Antel, J.P., Newcombe, J., Chen, Z., Freedman, M., Blain, M., Cayrol, R., Prat, A., Hall, J.A., Arbour, N. J. Neurosci. (2007) [Pubmed]
  30. TNFalpha stimulates NKG2D-mediated lytic activity of acute myeloid leukemic cells. Guilloton, F., de Thonel, A., Jean, C., Demur, C., Mansat-De Mas, V., Laurent, G., Quillet-Mary, A. Leukemia (2005) [Pubmed]
  31. Proteolytic release of soluble UL16-binding protein 2 from tumor cells. Waldhauer, I., Steinle, A. Cancer Res. (2006) [Pubmed]
  32. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Castriconi, R., Cantoni, C., Della Chiesa, M., Vitale, M., Marcenaro, E., Conte, R., Biassoni, R., Bottino, C., Moretta, L., Moretta, A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  33. Placenta-derived soluble MHC class I chain-related molecules down-regulate NKG2D receptor on peripheral blood mononuclear cells during human pregnancy: a possible novel immune escape mechanism for fetal survival. Mincheva-Nilsson, L., Nagaeva, O., Chen, T., Stendahl, U., Antsiferova, J., Mogren, I., Hernestål, J., Baranov, V. J. Immunol. (2006) [Pubmed]
  34. Expression of the NKG2D ligand UL16 binding protein-1 (ULBP-1) on dendritic cells. Schrama, D., Terheyden, P., Otto, K., Kämmerer, U., Bröcker, E.B., Lühder, F., Cosman, D., Andersen, M.H., Becker, J.C. Eur. J. Immunol. (2006) [Pubmed]
  35. Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D. Bacon, L., Eagle, R.A., Meyer, M., Easom, N., Young, N.T., Trowsdale, J. J. Immunol. (2004) [Pubmed]
  36. Human NK cytotoxicity against porcine cells is triggered by NKp44 and NKG2D. Forte, P., Lilienfeld, B.G., Baumann, B.C., Seebach, J.D. J. Immunol. (2005) [Pubmed]
  37. Differential expression of inhibitory and activating CD94/NKG2 receptors on NK cell clones. Brostjan, C., Bellón, T., Sobanov, Y., López-Botet, M., Hofer, E. J. Immunol. Methods (2002) [Pubmed]
  38. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Bauer, S., Groh, V., Wu, J., Steinle, A., Phillips, J.H., Lanier, L.L., Spies, T. Science (1999) [Pubmed]
  39. NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells. Upshaw, J.L., Arneson, L.N., Schoon, R.A., Dick, C.J., Billadeau, D.D., Leibson, P.J. Nat. Immunol. (2006) [Pubmed]
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