KLRK1 gene

The KLRK1 gene (KLRK1 stands for: Killer Cell Lectin Like Receptor K1) also called NKG2 gene (NKG2 stands for: Nataural Killer Group 2) is a protein-coding gene located on chromosome 12p13.2. Gene Ontology (GO) annotations associated with this gene include signaling receptor activity and carbohydrate binding. An important paralog of this gene is OLR1.

Natural killer cells (NK cells) are lymphocytes that can mediate the lysis of certain tumor cells and virus-infected cells without prior activation. They can also regulate specific humoral and cell-mediated immunity. NK cells preferentially express several calcium-dependent (C-type) lectins that are involved in the regulation of NK cell function. The NKG2 gene family is located within the NK complex, a region containing several C-type lectin genes that are preferentially expressed in NK cells.

The KLRK1 gene encodes a member of the NKG2 family. The encoded transmembrane protein is characterized by a type II membrane orientation (with an extracellular C-terminus) and the presence of a C-type lectin domain. It binds to a diverse family of ligands, including MHC class I chain-related A and B proteins and UL-16-binding proteins, whereby ligand-receptor interactions can lead to activation of NK and T cells.

The surface expression of these ligands is important for the recognition of damaged (stressed) cells by the immune system, which is why this protein and its ligands are therapeutic targets for the treatment of immune and tumor diseases. Read-through transcription occurs between this gene and the upstream family member KLRC4 (Killer Cell Lectin-Like Receptor Subfamily C, Member 4) in the same cluster.

Diseases associated with KLRK1 include cowpox and celiac disease. Associated signaling pathways include DAP12 interactions and the innate immune system.

Functions as an activating and costimulatory receptor involved in immune surveillance by binding to various cellular stress-inducible ligands expressed on the surface of autologous tumor cells and virus-infected cells. Mediates both stimulatory and costimulatory innate immune responses to activated killer cells (NK cells), leading to cytotoxic activity. Acts as a costimulatory receptor for the T cell receptor (TCR) in CD8(+) T cell-mediated adaptive immune responses by enhancing T cell activation. Stimulates perforin-mediated elimination of ligand-expressing tumor cells. Signaling involves the influx of calcium, culminating in the expression of TNF-alpha. Involved in NK cell-mediated rejection of bone marrow transplants. May play a regulatory role in the differentiation and survival of NK cells. Binds to ligands belonging to various subfamilies of MHC class I-related glycoproteins, including MICA, MICB, RAET1E, RAET1G, RAET1L/ULBP6, ULBP1, ULBP2, ULBP3 (ULBP2>ULBP1>ULBP3) and ULBP4.

1. Iwaszko M et al. (2011) Clinical significance of the HLA-E and CD94/NKG2 interaction. Arch Immunol Ther Exp (Warsz) 59:353-367.
2. Lanier LL (2015) NKG2D Receptor and Its Ligands in Host Defense. Cancer Immunol Res 3:575-582.