KLRK1 Gene (NKG2D): Function, Expression, and Clinical Significance | Biomedical Resource

KLRK1 encodes NKG2D, a type II transmembrane C-type lectin-like receptor expressed on natural killer (NK) cells, CD8+ T cells, and subsets of γδ T cells. NKG2D functions as an activating receptor that recognizes stress-induced ligands (e.g., MICA, MICB, ULBP family) on tumor cells and infected cells, triggering cytotoxic responses and cytokine production. It plays a critical role in immune surveillance, tumor rejection, and antiviral defense. The gene is located on chromosome 12p13.2 and is part of the NK gene complex. Alternative splicing produces multiple isoforms, and the receptor can be expressed as a membrane-bound or soluble form, with soluble NKG2D potentially modulating immune responses.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• NK cell mediated cytotoxicity (KEGG hsa04650)

• Natural killer cell signaling (Reactome R-HSA-1236977)

• Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (Reactome R-HSA-198933)

• Antigen processing and presentation (partially)

NKG2D is a type II transmembrane protein with an extracellular C-type lectin-like domain that forms homodimers. It associates with DAP10 (HCST) adaptor protein via a charged residue in its transmembrane domain, leading to PI3K and GRB2 signaling. NKG2D recognizes stress-induced ligands such as MICA, MICB, and ULBP1-6, which are upregulated on transformed cells and infected cells. Upon ligand binding, NKG2D triggers NK cell cytotoxicity and co-stimulates T cells. The protein is also cleaved from the cell surface by matrix metalloproteinases, producing soluble NKG2D that can neutralize ligands and modulate immune responses. Post-translational modifications include glycosylation and disulfide bond formation.