KLRK1 (killer cell lectin-like receptor subfamily K, member 1)

2014-06-01   Lewis L Lanier 

UCSF, Department of Microbiology, Immunology, San Francisco, CA 94143-0414, USA




KLRK1 encodes a type II transmembrane-anchored glycoprotein that is expressed as a disulfide-linked homodimer on the surface of Natural Killer (NK) cells, gamma\/delta TcR+ T cells, CD8+ T cells, and a minor subset of CD4+ T cells. It associates non-covalently with the DAP10 signaling protein and provides activating or costimulatory signals to NK cells and T cells. NKG2D binds to a family of glycoproteins, in humans the MICA, MICB, and ULBP1-6 membrane proteins, which are frequently expressed on cells that have become infected with pathogens or undergone transformation.



KLRK1 is present on chromosome 12 within a cluster of genes referred to as the "NK complex" (NKC) because several genes that are preferentially expressed by Natural Killer (NK) cells are located in this region, including on the centromeric side KLRD1 (CD94) and on the telomeric side KLRC4 (NKG2F), KLRC3 (NKG2E), KLRC2 (NKG2C), and KLRC1 (NKG2A) (Houchins et al., 1991).
Atlas Image
Schematic representation of the KLRC2 (NKG2C), KLR3 (NKG2E), KLRC4 (NKG2F), and KLRK1 genes on human chromosome 12p13.2 (taken from Glienke et al., 1998, figure 4).


The KLRK1 gene is 17702 bases located on the negative strand of chromosome 12 spanning bases 10372353 to 103900054 with a predicted 7 exons.


There is evidence for alternative splicing of KLRK1, but only one isoform encoding a functional protein has been described in humans. In one of the KLRK1 splice variants the fourth exon of KLRC4 is spliced to the 5-prime end of KLRK1. KLRK1 is transcribed by NK cells, gamma/delta-TcR+ T cells, CD8+ T cells and some CD4+ T cells (Bauer et al., 1999). Transcription of KLRK1 is enhanced by stimulation of NK cells with IL-2 or IL-15 and decreased by culture with TGF-beta.


No known pseudogenes.



KLRK1 is a type II transmembrane-anchored membrane glycoprotein expressed as a disulfide-bonded homodimer on the cell surface. Expression of KLRK1 on the cell surface requires its association with DAP10, which is a type I adapter protein expressed as a disulfide-bonded homodimer (Wu et al., 1999). On the cell surface, the receptor complex is a hexamer; two disulfide-bonded KLRK1 homodimers each paired with two DAP10 disulfide-bonded homodimers (Garrity et al., 2005). A charged amino acid residue (aspartic acid) centrally located within the transmembrane region of DAP10 forms a salt bridge with a charged amino acid residue (arginine) in the transmembrane region of KLRK1 to stabilize the receptor complex (Wu et al., 1999).
Atlas Image
Amino acid sequence of KLRK1 is shown, with the predicted transmembrane domain underlined. The R residue in the transmembrane is required for association of KLRK1 with the DAP10 signaling protein to form the mature receptor complex. Three potential sites for N-linked glycosylation are in bold.


KLRK1 is a type II membrane protein comprising 216 amino acids with a predicted molecular weight of 25,143 kDa. The protein has an N-terminal intracellular region, a transmembrane domain, a membrane-proximal stalk region, and an extracellular region with a single C-type lectin-like domain. KLRK1 is expressed on the cell surface as a disulfide-bonded homodimer with a molecular weight of approximately 42 kDa when analyzed under reducing conditions and approximately 80 kDa under non-reducing conditions. A cysteine residue just outside the transmembrane region forms the disulfide bond joining the two subunits of the homodimer. There are three potential sites for N-linked glycosylation in the extracellular region of KLRK1. Treatment of the KLRK1 glycoprotein with N-glycanase reduces the molecular weight to approximately the size of the core polypeptide.
Atlas Image
Schematic representation of the KLRK1 (NKG2D) - DAP10 receptor complex (taken from Garrity et al., 2005, figure 7).


KLRK1 protein is expressed on the cell surface of NK cells, gamma/delta-TcR+ T cells, CD8+ T cells, and some CD4+ T cells (Bauer et al., 1999).


KLRK1 is expressed as a type II integral membrane glycoprotein on the cell surface of NK cells, gamma/delta-TcR+ T cells, CD8+ T cells, and some CD4+ T cells (Bauer et al., 1999). In the absence of DAP10, KLRK1 protein is retained in the cytoplasm and degraded (Wu et al., 1999).


KLRK1 binds to at least eight distinct ligands: MICA, MICB, ULBP-1, ULBP-2, ULBP-3, ULBP-4, ULBP-5, and ULBP-6 (Bauer et al., 1999; Cosman et al., 2001; Raulet et al., 2013). These ligands are type I glycoproteins with homology to MHC class I. The KLRK1 ligands frequently are over-expressed on tumor cells, virus-infected cells, and "stressed" cells (Raulet et al., 2013). The crystal structure of KLRK1 bound to MICA has been described (Li et al., 2001). After binding to its ligand, KLRK1 transmits an activating signal via the DAP10 adapter subunit. DAP10 has a YINM motif in its cytoplasmic domain, which upon tyrosine phosphorylation binds to Vav and the p85 subunit of PI3-kinase (Billadeau et al., 2003; Wu et al., 1999), causing a downstream cascade of signaling in T cells and NK cells, resulting in the killing of ligand-bearing cells and the secretion of cytokines by NK cells and T cells.
Atlas Image
Structure of the KLRK1 homodimer (a) and its ligand MICA (b) (taken from Li et al., 2001, figure 1).


Pan troglodytes: NP_001009059
Macaca mulatta: NP_001028061
Macaca fascicularis: CAD19993
Callithrix jacchus: ABN45890
Papio anubis: ABO09749
Pongo pygmaeus: Q8MJH1
Bos taurus: CAJ27114
Sus scrofa: Q9GLF5
Mus musculus: NP_149069
Mus musculus: NP_001076791
Rattus norvegicus: NP_598196
Callithrix jacchus: A4GHD0
Neovison vison: U6DVF4
Microcebus murinus: D1GEY1
Varecia variegate: D1GF00
Lithobates catesbeiana: C1C4X9



None identified.

Implicated in

Entity name
Many types of cancer (carcinomas, sarcomas, lymphomas, and leukemias) over-express the ligands for KLRK1 (Raulet et al., 2013). In some cases, this renders the tumor cells susceptible to killing by activated KLRK1-bearing NK cells. Some tumors shed or secrete soluble ligands that bind to KLRK1, which downregulates expression of KLRK1 on NK cells and T cells (Groh et al., 2002), although the physiological relevance of the shed ligands is controversial. Mice in which the Klrk1 gene has been disrupted show increased susceptibility to certain cancers caused by transgenic expression of oncogenes (Guerra et al., 2008).
Entity name
Viral infection
Viral infection of cells can induce transcription and cell surface expression of ligands for KLRK1, rendering these infected cells susceptible to attack by NK cells and T cells (Champsaur and Lanier, 2010; Raulet et al., 2013). Some viruses, for example cytomegalovirus, encode proteins that intercept the ligand proteins intracellularly and prevent their expression on the surface of virus-infected cells.
Entity name
Rheumatoid arthritis
An expansion of CD4+,CD28- T cells expressing KLRK1 was observed in the joints of patients with rheumatoid arthritis and KLRK1 ligands were detected on synovial cells in the inflamed tissue (Groh et al., 2003).
Entity name
Type I diabetes
Peripheral blood NK cells and T cells in patients with type I diabetes demonstrate a slightly decreased amount of expression of KLRK1 on the cell surface, independent disease duration (Rodacki et al., 2007), similar to prior observations in the NOD mouse (Ogasawara et al., 2003).


Pubmed IDLast YearTitleAuthors
104269931999Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.Bauer S et al
127405752003NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway.Billadeau DD et al
205365692010Effect of NKG2D ligand expression on host immune responses.Champsaur M et al
112394452001ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor.Cosman D et al
158946122005The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure.Garrity D et al
96836611998The genomic organization of NKG2C, E, F, and D receptor genes in the human natural killer gene complex.Glienke J et al
128787252003Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis.Groh V et al
123847022002Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation.Groh V et al
183949362008NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy.Guerra N et al
20078501991DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells.Houchins JP et al
113236992001Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA.Li P et al
125309742003Impairment of NK cell function by NKG2D modulation in NOD mice.Ogasawara K et al
232982062013Regulation of ligands for the NKG2D activating receptor.Raulet DH et al
171924802007Altered natural killer cells in type 1 diabetic patients.Rodacki M et al
104269941999An activating immunoreceptor complex formed by NKG2D and DAP10.Wu J et al

Other Information

Locus ID:

NCBI: 22914
MIM: 611817
HGNC: 18788
Ensembl: ENSG00000213809


dbSNP: 22914
ClinVar: 22914
TCGA: ENSG00000213809


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Natural killer cell mediated cytotoxicityKEGGko04650
Natural killer cell mediated cytotoxicityKEGGhsa04650
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cellREACTOMER-HSA-198933
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
123847022002Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation.436
145233852003Roles of the NKG2D immunoreceptor and its ligands.400
183949362008NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy.278
232982062013Regulation of ligands for the NKG2D activating receptor.253
184907242008Human tumor-derived exosomes down-modulate NKG2D expression.184
126467002003Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells.170
151871092004Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients.154
193192002009Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha.118
150706862004Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells.116
178756812007The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells.103


Lewis L Lanier

KLRK1 (killer cell lectin-like receptor subfamily K, member 1)

Atlas Genet Cytogenet Oncol Haematol. 2014-06-01

Online version: http://atlasgeneticsoncology.org/gene/41094/klrk1-(killer-cell-lectin-like-receptor-subfamily-k-member-1)

Historical Card

2007-07-01 KLRK1 (killer cell lectin-like receptor subfamily K, member 1) by  Lewis L Lanier 

UCSF, Department of Microbiology, Immunology, San Francisco, CA 94143-0414, USA