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Killer cell lectin-like receptor subfamily K, member 1
Protein KLRK1 PDB 1hyr.png
PDB rendering based on 1hyr.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols KLRK1 ; CD314; D12S2489E; KLR; NKG2-D; NKG2D
External IDs OMIM611817 MGI1196250 HomoloGene136440 GeneCards: KLRK1 Gene
Species Human Mouse
Entrez 22914 27007
Ensembl ENSG00000213809 ENSMUSG00000030149
UniProt P26718 O54709
RefSeq (mRNA) NM_007360 NM_001083322
RefSeq (protein) NP_031386 NP_001076791
Location (UCSC) Chr 12:
10.52 – 10.54 Mb
Chr 6:
129.61 – 129.62 Mb
PubMed search [1] [2]

NKG2D is an activating receptor found on NK cells and CD8 T cells (both αβ and γδ) which was first identified in 1991[1] and is encoded by the KLRK1 gene. Its function as an activating receptor was first described in 1999,[2] and its ligands are stress-induced proteins such as MICA, MICB, ULBP1, ULBP2, ULBP3, and ULBP4-6 for human NKG2D, and Rae-1, Mult1, and H-60 for murine NKG2D.[3]


The structure of NKG2D consists of two disulphide-linked type II transmembrane proteins with short intracellular domains incapable of transducing signals. They therefore require adaptor proteins in order to transduce signals, and this receptor uses two adapter proteins, DAP10 and DAP12, which associate as homodimers to the receptor - therefore the entire receptor complex appears as a hexamer.[4]


The ligands for NKG2D are induced during times of cellular stress, either as a result of infection or genomic stress such as in cancer, which renders the cell susceptible to NK cell mediated lysis. The function of NKG2D on CD8 T cells is to send co-stimulatory signals to activate them.[5]

Role in viral infection[edit]

Viruses, as intracellular pathogens, can induce the expression of stress ligands for NKG2D. NKG2D is thought to be important in viral control as viruses have adapted mechanisms by which to evade NKG2D responses.[4] For example, cytomegalovirus (CMV) encodes a protein, UL16, which binds to NKG2D ligands ULBP1 and 2 (thus their name "UL16-binding protein") and MICB, which prevents their surface expression.[6]

Role in tumour control[edit]

As cancerous cells are "stressed", NKG2D ligands become upregulated, rendering the cell susceptible to NK cell-mediated lysis. Tumor cells that can evade NKG2D responses are thus more likely to propagate.[4]


  1. ^ Houchins JP, Yabe T, McSherry C, Bach FH (1991). "DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells.". J. Exp. Med. 173: 1017–1020. doi:10.1084/jem.173.4.1017. PMC 2190798. PMID 2007850. 
  2. ^ Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (1999). "Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.". Science 285 (5428): 727–729. doi:10.1126/science.285.5428.727. PMID 10426993. 
  3. ^ Raulet DH (October 2003). "Roles of the NKG2D immunoreceptor and its ligands". Nature Reviews Immunology 3: 781–79. doi:10.1038/nri1199. PMID 14523385. 
  4. ^ a b c Zafirova B, Wensveen FM, Gulin M, Polić B (2011). "Regulation of immune cell function and differentiation by the NKG2D receptor". Cell Mol Life Sci 68 (21): 3519–29. doi:10.1007/s00018-011-0797-0. PMC 3192283. PMID 21898152. 
  5. ^ González S, López-Soto A, Suarez-Alvarez B, López-Vázquez A, López-Larrea C (2008). "NKG2D ligands: key targets of the immune response". Trends in Immunology 29 (8). doi:10.1016/j.it.2008.04.007. PMID 18602338. 
  6. ^ Welte SA, Sinzger C, Lutz SZ, Singh-Jasuja H, Sampaio KL, Eknigk U, Rammensee HG, Steinle A (2003). "Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein". Eur J Immunol 33 (1): 194–203. doi:10.1002/immu.200390022. PMID 12594848.