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Gene Review

Klrk1  -  killer cell lectin-like receptor subfamily...

Mus musculus

Synonyms: D6H12S2489E, Killer cell lectin-like receptor subfamily K member 1, NK cell receptor D, NKG2-D, NKG2-D type II integral membrane protein, ...
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Disease relevance of Klrk1

  • The activation NKG2D receptor has been shown to play an important role in the control of experimental tumor growth and metastases expressing ligands for NKG2D; however, a function for this recognition pathway in host protection from de novo tumorigenesis has never been demonstrated [1].
  • Furthermore, IL-12 therapy preventing MCA-induced sarcoma formation was also largely dependent on the NKG2D pathway [1].
  • We show that neutralization of NKG2D enhances the sensitivity of wild-type (WT) C57BL/6 and BALB/c mice to methylcholanthrene (MCA)-induced fibrosarcoma [1].
  • NK cells use NKG2D to recognize a mouse renal cancer (Renca), yet require intercellular adhesion molecule-1 expression on the tumor cells for optimal perforin-dependent effector function [2].
  • These findings demonstrate that NKG2D is essential for disease progression and suggest a new therapeutic target for autoimmune type I diabetes [3].

High impact information on Klrk1

  • Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCR(dull) phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines [4].
  • Here we demonstrate that ectopic expression of the murine NKG2D ligands Rae1beta or H60 in several tumour cell lines results in potent rejection of the tumour cells by syngeneic mice [5].
  • Mice that are exposed to live or irradiated tumour cells expressing Rae1 or H60 are specifically immune to subsequent challenge with tumour cells that lack NKG2D ligands, suggesting application of the ligands in the design of tumour vaccines [5].
  • The stimulatory lectin-like NKG2D receptor is expressed by NK cells, activated CD8+ T cells and by activated macrophages in mice [5].
  • At the same time, it induced NKG2D ligand upregulation, which alerts the immune system to the presence of virally transformed cells [6].

Chemical compound and disease context of Klrk1


Biological context of Klrk1


Anatomical context of Klrk1

  • NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation [10].
  • We found that differential expression of these isoforms and of signaling proteins determined whether NKG2D functioned as a costimulatory receptor in the adaptive immune system (CD8+ T cells) or as both a primary recognition structure and a costimulatory receptor in the innate immune system (natural killer cells and macrophages) [14].
  • However, the precise mode of dimeric assembly varies among these natural killer receptors, as well as their surface topography and electrostatic properties.The NKG2D structure provides the first structural insights into the role and ligand specificity of this stimulatory receptor in the innate and adaptive immune system [15].
  • NKG2D is an important activating/co-stimulatory receptor harnessed by NK and T cells in immune surveillance [16].
  • However, for the R331 cell line established from Renca, NKG2D recognition and perforin-dependent lysis played no role in controlling liver metastases [2].

Associations of Klrk1 with chemical compounds


Physical interactions of Klrk1


Regulatory relationships of Klrk1


Other interactions of Klrk1

  • Although NKG2D ligand expression was variable or absent on sarcomas emerging in WT mice, sarcomas derived from perforin-deficient mice were Rae-1(+) and immunogenic when transferred into WT syngeneic mice [1].
  • The Ly49I monomer adopts a fold similar to that of other C-type lectin-like NK receptors, including Ly49A, NKG2D and CD69 [27].
  • This result excludes Cd94 and Nkg2d as candidates whereas it localizes the Ly49 genes within the minimal genetic interval for Cmv1 [28].
  • NKG2I, which was composed of 226 amino acids, showed approximately 40% homology to the murine NKG2D and CD94 in the C-type lectin domain [29].
  • Here we show that the magnitude of NKG2D-mediated cytotoxicity is directly proportional to both the levels of H60 and the nature of major histocompatibility complex (MHC) class I molecules expressed on the target cells [30].

Analytical, diagnostic and therapeutic context of Klrk1


  1. NKG2D function protects the host from tumor initiation. Smyth, M.J., Swann, J., Cretney, E., Zerafa, N., Yokoyama, W.M., Hayakawa, Y. J. Exp. Med. (2005) [Pubmed]
  2. NK cells use NKG2D to recognize a mouse renal cancer (Renca), yet require intercellular adhesion molecule-1 expression on the tumor cells for optimal perforin-dependent effector function. Abdool, K., Cretney, E., Brooks, A.D., Kelly, J.M., Swann, J., Shanker, A., Bere, E.W., Yokoyama, W.M., Ortaldo, J.R., Smyth, M.J., Sayers, T.J. J. Immunol. (2006) [Pubmed]
  3. NKG2D blockade prevents autoimmune diabetes in NOD mice. Ogasawara, K., Hamerman, J.A., Ehrlich, L.R., Bour-Jordan, H., Santamaria, P., Bluestone, J.A., Lanier, L.L. Immunity (2004) [Pubmed]
  4. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Moretta, A., Bottino, C., Vitale, M., Pende, D., Cantoni, C., Mingari, M.C., Biassoni, R., Moretta, L. Annu. Rev. Immunol. (2001) [Pubmed]
  5. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Diefenbach, A., Jensen, E.R., Jamieson, A.M., Raulet, D.H. Nature (2001) [Pubmed]
  6. A role for activation-induced cytidine deaminase in the host response against a transforming retrovirus. Gourzi, P., Leonova, T., Papavasiliou, F.N. Immunity (2006) [Pubmed]
  7. NKG2D-mediated natural killer cell protection against cytomegalovirus is impaired by viral gp40 modulation of retinoic acid early inducible 1 gene molecules. Lodoen, M., Ogasawara, K., Hamerman, J.A., Arase, H., Houchins, J.P., Mocarski, E.S., Lanier, L.L. J. Exp. Med. (2003) [Pubmed]
  8. NK cell activation through the NKG2D ligand MULT-1 is selectively prevented by the glycoprotein encoded by mouse cytomegalovirus gene m145. Krmpotic, A., Hasan, M., Loewendorf, A., Saulig, T., Halenius, A., Lenac, T., Polic, B., Bubic, I., Kriegeskorte, A., Pernjak-Pugel, E., Messerle, M., Hengel, H., Busch, D.H., Koszinowski, U.H., Jonjic, S. J. Exp. Med. (2005) [Pubmed]
  9. Interleukin 2 gene transfer prevents NKG2D suppression and enhances antitumor efficacy in combination with cisplatin for head and neck squamous cell cancer. Li, D., Ronson, B., Guo, M., Liu, S., Bishop, J.S., Van Echo, D.A., O'Malley, B.W. Cancer Res. (2002) [Pubmed]
  10. NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Gilfillan, S., Ho, E.L., Cella, M., Yokoyama, W.M., Colonna, M. Nat. Immunol. (2002) [Pubmed]
  11. Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells. Ho, E.L., Heusel, J.W., Brown, M.G., Matsumoto, K., Scalzo, A.A., Yokoyama, W.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  12. Crystal structures of RAE-1beta and its complex with the activating immunoreceptor NKG2D. Li, P., McDermott, G., Strong, R.K. Immunity (2002) [Pubmed]
  13. Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Oppenheim, D.E., Roberts, S.J., Clarke, S.L., Filler, R., Lewis, J.M., Tigelaar, R.E., Girardi, M., Hayday, A.C. Nat. Immunol. (2005) [Pubmed]
  14. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Diefenbach, A., Tomasello, E., Lucas, M., Jamieson, A.M., Hsia, J.K., Vivier, E., Raulet, D.H. Nat. Immunol. (2002) [Pubmed]
  15. Crystal structure of the murine NK cell-activating receptor NKG2D at 1.95 A. Wolan, D.W., Teyton, L., Rudolph, M.G., Villmow, B., Bauer, S., Busch, D.H., Wilson, I.A. Nat. Immunol. (2001) [Pubmed]
  16. T cells gene-engineered with DAP12 mediate effector function in an NKG2D-dependent and major histocompatibility complex-independent manner. Teng, M.W., Kershaw, M.H., Hayakawa, Y., Cerutti, L., Jane, S.M., Darcy, P.K., Smyth, M.J. J. Biol. Chem. (2005) [Pubmed]
  17. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Cerwenka, A., Bakker, A.B., McClanahan, T., Wagner, J., Wu, J., Phillips, J.H., Lanier, L.L. Immunity (2000) [Pubmed]
  18. Immunodominance of H60 is caused by an abnormally high precursor T cell pool directed against its unique minor histocompatibility antigen peptide. Choi, E.Y., Christianson, G.J., Yoshimura, Y., Sproule, T.J., Jung, N., Joyce, S., Roopenian, D.C. Immunity (2002) [Pubmed]
  19. Impairment of NK cell function by NKG2D modulation in NOD mice. Ogasawara, K., Hamerman, J.A., Hsin, H., Chikuma, S., Bour-Jordan, H., Chen, T., Pertel, T., Carnaud, C., Bluestone, J.A., Lanier, L.L. Immunity (2003) [Pubmed]
  20. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Radaeva, S., Sun, R., Jaruga, B., Nguyen, V.T., Tian, Z., Gao, B. Gastroenterology (2006) [Pubmed]
  21. Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells. Rabinovich, B.A., Li, J., Shannon, J., Hurren, R., Chalupny, J., Cosman, D., Miller, R.G. J. Immunol. (2003) [Pubmed]
  22. Cutting edge: the minor histocompatibility antigen H60 peptide interacts with both H-2Kb and NKG2D. Cerwenka, A., O'Callaghan, C.A., Hamerman, J.A., Yadav, R., Ajayi, W., Roopenian, D.C., Joyce, S., Lanier, L.L. J. Immunol. (2002) [Pubmed]
  23. H60/TNT-3 fusion protein activates NK cells in vitro and improves immunotherapeutic outcome in murine syngeneic tumor models. Flanagan, M.L., Khawli, L.A., Hu, P., Epstein, A.L. J. Immunother. (2006) [Pubmed]
  24. NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer. Smyth, M.J., Swann, J., Kelly, J.M., Cretney, E., Yokoyama, W.M., Diefenbach, A., Sayers, T.J., Hayakawa, Y. J. Exp. Med. (2004) [Pubmed]
  25. The cytomegalovirus m155 gene product subverts natural killer cell antiviral protection by disruption of H60-NKG2D interactions. Lodoen, M.B., Abenes, G., Umamoto, S., Houchins, J.P., Liu, F., Lanier, L.L. J. Exp. Med. (2004) [Pubmed]
  26. Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy. Zhang, T., Lemoi, B.A., Sentman, C.L. Blood (2005) [Pubmed]
  27. Crystal structure of the Ly49I natural killer cell receptor reveals variability in dimerization mode within the Ly49 family. Dimasi, N., Sawicki, M.W., Reineck, L.A., Li, Y., Natarajan, K., Margulies, D.H., Mariuzza, R.A. J. Mol. Biol. (2002) [Pubmed]
  28. Assessment of Cmv1 candidates by genetic mapping and in vivo antibody depletion of NK cell subsets. Depatie, C., Chalifour, A., Paré, C., Lee, S.H., Vidal, S.M., Lemieux, S. Int. Immunol. (1999) [Pubmed]
  29. Bone marrow allograft rejection mediated by a novel murine NK receptor, NKG2I. Koike, J., Wakao, H., Ishizuka, Y., Sato, T.A., Hamaoki, M., Seino, K., Koseki, H., Nakayama, T., Taniguchi, M. J. Exp. Med. (2004) [Pubmed]
  30. NKG2D receptor-mediated NK cell function is regulated by inhibitory Ly49 receptors. Regunathan, J., Chen, Y., Wang, D., Malarkannan, S. Blood (2005) [Pubmed]
  31. Function of NKG2D in natural killer cell-mediated rejection of mouse bone marrow grafts. Ogasawara, K., Benjamin, J., Takaki, R., Phillips, J.H., Lanier, L.L. Nat. Immunol. (2005) [Pubmed]
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