NCR2

What is NCR2 protein?

NCR2 gene (natural cytotoxicity triggering receptor 2) is a protein coding gene which situated on the short arm of chromosome 6 at locus 6p21. NCR2 is a protein that plays a role in the immune system. It is mainly expressed on natural killer (NK) cells and certain T cells, and is involved in regulating the activity of these cells, thus playing a role in the immune response. The NCR2 protein (or NKp44) activates NK cells and T cells by recognizing and binding to specific ligands on the surface of target cells, such as stress-induced ligands, which in turn exert cytotoxic effects to help clear infected or tumor cells. The NCR2 protein is consisted of 276 amino acids and NCR2 molecular weight is approximately 30.7 kDa.

What is the function of NCR2 protein?

According to The Human Protein Atlas, NCR2 protein is expressed in a variety of tissues and may be involved in a variety of biological processes in different cell types, such as cell proliferation, signaling, immune response, and metabolism. By binding to ligands on the surface of target cells, NCR2 triggers cytotoxic effects on NK cells and T cells, leading to the cleavage of target cells. NCR2 is involved in the immune system's surveillance of abnormal cells, helping to clear tumor cells and virus-infected cells in time. NCR2 may be involved in regulating the intensity and duration of the immune response, affecting the activation and function of immune cells.

Fig1. Expression of the NCRs and their Ligands. (Alexander David Barrow, 2019)

NCR2 related signaling pathway

Signaling of NCR2 protein is mainly achieved through non-covalent binding to DNAx-activating protein 12kDa (DAP12), which contains the immunoreceptor tyrosine activating motif (ITAM). When NCR2 binds to its ligand, ITAM of DAP12 is phosphorylated by Src kinase, which recruits Syk kinase. Activation of downstream signaling molecules, such as phosphatidylinositol 3 kinase (PI3K), phospholipase Cγ2 (PLCγ2), VAV family exchange factors. These signaling events ultimately lead to cytoskeletal remodeling, cytokine production, and cytotoxicity.

NCR2 related diseases

The NCR2 protein is associated with a variety of diseases, particularly in the field of oncology, where it plays a key role in the activation of natural killer (NK) cells, helping to identify and remove tumor cells. The expression of NCR2 ligands on a variety of tumor cells makes it play an important role in tumor immune surveillance, but its expression in the tumor microenvironment may also be inhibited, affecting the anti-tumor activity of NK cells. In addition, NCR2 may be associated with viral infections because of its ability to recognize and respond to certain viral components. In autoimmune diseases, the function of NCR2 may also be affected, although its role in these diseases is not fully understood.

Bioapplications of NCR2

Recombinant human NCR2 (rhNCR2) protein has wide application prospect in biomedical field. It is primarily used in immunotherapy, especially in cancer treatment, to identify and eliminate tumor cells by enhancing the activity of natural killer (NK) cells. In addition, the rhNCR2 protein can also be used to optimize cell therapy by tracking the movement of stem cells and immune cells to provide a basis for cell therapy. In NIR two-region fluorescence imaging technology, rhNCR2 protein can be combined with fluorescent labeling for living cell tracing, helping to study the cell movement trajectory and pathophysiological processes in vivo, and then finding treatment options.

Case Study 1: Benedetta Padoan, 2024

Natural killer (NK) cells play a role in tuning immune responses, but the specifics of this regulation are not fully understood. This study shows that the expression of human leukocyte antigen (HLA)-DP, which binds to the activating receptor NKp44 on NK cells, is notably increased on CD8+ effector T cells in individuals infected with human cytomegalovirus (HCMV). When CD8+ T cells display HLA-DP antigens that can bind to NKp44, they activate NKp44+ NK cells. Conversely, CD8+ T cells without these NKp44-binding HLA-DP antigens fail to activate NK cells. Consistent with this, people lacking the genetic makeup for NKp44-binding HLA-DP have more of these HLA-DP+ CD8+ T cells, which can lead to the overexpansion of T cell clones, compared to those with NKp44-binding HLA-DP.

Fig1. Representative flow cytometric plot showing NKp44-Fc construct binding to HLA-DP−/+ CD8+ T cells.

Fig2. Median percentage of HLA-DP+ CD8+ T cells from individuals with two NKp44-NB.

Case Study 2: Kerstin H Mair, 2022

Natural killer (NK) cells are crucial for the innate immune system in humans and mice, quickly targeting tumors or virus-infected cells. Key for this function are the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. While NKp44 is known to activate human NK cells, its role in pigs was unknown due to a lack of specific antibodies. This study developed porcine-specific anti-NKp44 antibodies, revealing that NKp44 is expressed not only on activated but also on resting NK cells in pigs. Moreover, NKp44+ cells are more prevalent than NKp46+ cells. Stimulation with IL-2 or IL-15 boosts both the number and activation of NKp44+ NK cells. These findings, made possible by the creation of a new monoclonal antibody (mAb), will help clarify the development and function of pig NK cells.

Fig3. HEK293T cells were transiently transfected with a mammalian expression vector containing the sequence of porcine NKp44 with an N-terminal FLAG tag.

Fig4. Frequencies of NKp44+ cells within total NK cells for all animals.

NCR2 has several biochemical functions, for example, transmembrane signaling receptor activity. Some of the functions are cooperated with other proteins, some of the functions could acted by NCR2 itself. We selected most functions NCR2 had, and list some proteins which have the same functions with NCR2. You can find most of the proteins on our site.

NCR2 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with NCR2 here. Most of them are supplied by our site. Hope this information will be useful for your research of NCR2.