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NCR3
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NCR3
Natural cytotoxicity triggering receptor 3 is a protein that in humans is encoded by the NCR3 gene. NCR3 has also been designated as CD337 (cluster of differentiation 337) and as NKp30. NCR3 belongs to the family of NCR membrane receptors together with NCR1 (NKp46) and NCR2 (NKp44).
NKp30 receptor was first identified in 1999. According to Western blot analysis specific monoclonal antibodies reacted with 30kDa molecule, therefore was the protein named NKp30.
Gene for NKp30 is located in the MHC class III region of the human MHC locus and encodes 190 amino acid long type I transmembrane receptor which belongs to immunoglobulin super family (IgSF). NKp30 has a mass of 30 kDa and includes one Ig-like extracellular domain which is 138 amino acids long, a 19 amino acid transmembrane (TM) domain and a 33 amino acid cytoplasmic tail. The Ig-like domain consists of 2 antiparallel beta-sheets linked by a disulphide bond. The extracellular domain contains two potential sites for N-linked glycosylation involved in ligand binding. The TM domain contains a positivelly charged arginine residue, which associates with negatively charged aspartate in TM domain of ITAM adaptor molecules CD3ζ and FCεRIγ. This is a common feature of other NK cell activating receptors as well. Accordingly the cytoplasmic tail lacks typical ITAM consensus sequence.
Six different splicing variants can be found on the cell surface. NKp30a, NKp30b and NKp30c encode molecules with extracellular V-type Ig domain. NKp30d, NKp30e and NKp30f encode extracellular C-type Ig domain. Splicing variants also differ in their cytosolic intracellular domains depending on the translation of variants of exon 4 (NKp30a,b or c).
The distribution of splicing variants of NKp30 varies in tissues and results in different NK cell responses. NKp30a/b engagement stimulates the release of high amounts of IFN-γ, whereas activation of NKp30c induces IL-10 production and only small amounts of IFN-γ. First two are therefore considered as immunostimulatory isoforms which enhance Th1 immune response, while NKp30c mediates immunosuppressive signaling most likely because of reduced association with CD3ζ adaptor after cross-linking with ligand.
Gastrointestinal stromal tumor patients who express NKp30c isoform have worse prognosis compared with patients expressing other isoforms, mainly as a consequence of NK cell immunosuppressive character.
NCR3 is expressed mainly on cytoplasmic membrane of mature NK cells and functions as an activating receptor of NK cells. However it is also expressed on surface of CD8+ T cells, γδ T cells with Vδ1 TCR and ILC2. The presence of IL-15 stimulates the expression of NKp30+ CD8+ T cells with anti-tumor activity. Expression of NKp30 in γδ T cells is induced by IL-2 or IL-15. After progesteron stimulation NKp30 can be found on the cytoplasmic membrane of endometrial epithelial cells as well.
NKp30 plays a major role in NK anti-tumor response and immunosurveillance, mainly by activating NK cell cytotoxicity and cytokine secretion. Direct killing happens similarly to other natural cytotoxicity receptors (NCRs) such as NKp44 and NKp46. NCR3 has a wide range of non-MHC ligands secreted or expressed by cancer or virus-infected cells, e.g. to heparan sulfate glycosaminoglycans (HS GAGs) and B7-H6.
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NCR3
Natural cytotoxicity triggering receptor 3 is a protein that in humans is encoded by the NCR3 gene. NCR3 has also been designated as CD337 (cluster of differentiation 337) and as NKp30. NCR3 belongs to the family of NCR membrane receptors together with NCR1 (NKp46) and NCR2 (NKp44).
NKp30 receptor was first identified in 1999. According to Western blot analysis specific monoclonal antibodies reacted with 30kDa molecule, therefore was the protein named NKp30.
Gene for NKp30 is located in the MHC class III region of the human MHC locus and encodes 190 amino acid long type I transmembrane receptor which belongs to immunoglobulin super family (IgSF). NKp30 has a mass of 30 kDa and includes one Ig-like extracellular domain which is 138 amino acids long, a 19 amino acid transmembrane (TM) domain and a 33 amino acid cytoplasmic tail. The Ig-like domain consists of 2 antiparallel beta-sheets linked by a disulphide bond. The extracellular domain contains two potential sites for N-linked glycosylation involved in ligand binding. The TM domain contains a positivelly charged arginine residue, which associates with negatively charged aspartate in TM domain of ITAM adaptor molecules CD3ζ and FCεRIγ. This is a common feature of other NK cell activating receptors as well. Accordingly the cytoplasmic tail lacks typical ITAM consensus sequence.
Six different splicing variants can be found on the cell surface. NKp30a, NKp30b and NKp30c encode molecules with extracellular V-type Ig domain. NKp30d, NKp30e and NKp30f encode extracellular C-type Ig domain. Splicing variants also differ in their cytosolic intracellular domains depending on the translation of variants of exon 4 (NKp30a,b or c).
The distribution of splicing variants of NKp30 varies in tissues and results in different NK cell responses. NKp30a/b engagement stimulates the release of high amounts of IFN-γ, whereas activation of NKp30c induces IL-10 production and only small amounts of IFN-γ. First two are therefore considered as immunostimulatory isoforms which enhance Th1 immune response, while NKp30c mediates immunosuppressive signaling most likely because of reduced association with CD3ζ adaptor after cross-linking with ligand.
Gastrointestinal stromal tumor patients who express NKp30c isoform have worse prognosis compared with patients expressing other isoforms, mainly as a consequence of NK cell immunosuppressive character.
NCR3 is expressed mainly on cytoplasmic membrane of mature NK cells and functions as an activating receptor of NK cells. However it is also expressed on surface of CD8+ T cells, γδ T cells with Vδ1 TCR and ILC2. The presence of IL-15 stimulates the expression of NKp30+ CD8+ T cells with anti-tumor activity. Expression of NKp30 in γδ T cells is induced by IL-2 or IL-15. After progesteron stimulation NKp30 can be found on the cytoplasmic membrane of endometrial epithelial cells as well.
NKp30 plays a major role in NK anti-tumor response and immunosurveillance, mainly by activating NK cell cytotoxicity and cytokine secretion. Direct killing happens similarly to other natural cytotoxicity receptors (NCRs) such as NKp44 and NKp46. NCR3 has a wide range of non-MHC ligands secreted or expressed by cancer or virus-infected cells, e.g. to heparan sulfate glycosaminoglycans (HS GAGs) and B7-H6.
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