NKG2-D type II integral membrane protein (NKG2D) is a type II transmembrane glycoprotein which belongs to the CD94/NKG2 family. NKG2D is expressed on natural killer (NK) cells; CD8+ alpha-beta and gamma-delta T-cells. As an activating and costimulatory receptor; it involved in immunosurveillance upon binding to various cellular stress-inducible ligands displayed at the surface of autologous tumor cells and virus-infected cells. It provides both stimulatory and costimulatory innate immune responses on activated killer (NK) cells; leading to cytotoxic activity. It stimulates perforin-mediated elimination of ligand-expressing tumor cells. Signaling involves calcium influx; culminating in the expression of TNF-alpha. NKG2D participates in NK cell-mediated bone marrow graft rejection and survival of NK cells. It Binds to ligands belonging to various subfamilies of MHC class I-related glycoproteins including MICA; MICB; RAET1E; RAET1G; ULBP1; ULBP2; ULBP3 (ULBP2>ULBP1>ULBP3) and ULBP4.
NKG2D ligand 1; also called ULBP1; is a member of UL16-binding protein (ULBP) family which has also been termed the retinoic acid early transcript 1 (RAET1) family. Unlike the classical MHC class I molecules and the MIC molecules possess α1; α2 and α3 domains; ULBP/RAET1 family members lack α3 domain. ULBP1 is recognized by the activating receptor NKG2D on the surface of cytotoxic natural killer (NK) and T cells; and then promotes the lysis of cells expressing ULBP1 which is important for the immune surveillance. ULBP1 and several other family members; ULBP2 and ULBP5; own the ability to bind the human cytomegalovirus (CMV) UL16 glycoprotein. The human CMV glycoprotein UL16 binds to intracellular ULBP1 and so inhibits its expression at the cell surface; which reduces the susceptibility of the virus-infected cell to cytotoxic destruction by NK cells. The expression of ULBP1 has been found on some tumor cells and is implicated in tumor surveillance.
ULBP1; also known as RAET1I and NKG2DL1; is a member of the ULBP/RAET1 gene family. ULBP1 plays an important role in immune responses; especially in cancer and infectious diseases; and is well-known to bind to NKG2D together with at least ULBP 2 and 3. These proteins are distantly related to major histocompatibility class I (MHC I) molecules; possessing the alpha 1 and alpha 2 Ig-like domains; but lacking the alpha 3 domain. Unlike MHC Class I; they have no capacity to bind peptide or interact with beta2-microglobulin. It can activate multiple signaling pathways in primary NK cells; gamma delta T cells; and CD8+ alpha beta T cells; resulting in the production of cytokines and chemokines.ULBP1 is expressed in wide range of tissues including heart; brain; lung; liver; bone marrow and some tumor cells; T-cells; B-cells; As an unconventional member of the MHC class I family; ULBP1 is able to interact with soluble CMV glycoprotein UL16 in CMV infected cells. The interaction with UL16 blocked the interaction with the NKG2D receptor; and thus might escape the immune surveillance. Furthermore; UL16 also causes ULBP1 to be retained in the ER and cis-Golgi apparatus so that it does not reach the cell surface. The ULBP1 regulation may have implications for development of new therapeutic strategies against cancer cells.
Natural Cytotoxicity Triggering Receptor 3, NCR3, also known as NKp30, or CD337, is a natural cytotoxicity receptor, expressed on subsets of human peripheral blood NK cells, involved in NK cell killing of tumor cells and immature dendritic cells. The cellular ligand for NKp30 has remained elusive, but the membrane-associated heparan sulfate (HS) proteoglycans are involved in the recognition of cellular targets by NKp30 was recently reported. NKp30 is a member of the immunoglobulin superfamily and one of three existing natural cytotoxicity-triggering receptors. NKp30 is a glycosylated protein and is thought to be selectively expressed in resting and activated natural killer cells. NKp30 is a stimulatory receptor on human NK cells implicated in tumor immunity, and is capable of promoting or terminating dendritic cell maturation. NCR3 may play a role in inflammatory and infectious diseases.
Neuroligin 4, X-Linked (NLGN4X) is a single-pass type I membrane protein that belongs to the type-B carboxylesterase/lipase family. NLGN4X is detected at higher levels in heart and at lower levels in the liver, skeletal muscle, and pancreas. NLGN4X is a putative neuronal cell surface protein involved in cell-cell-interactions. NLGN4X may act as splice site-specific ligands for β-neurexins. It has been shown that NLGN4X is involved in the formation and remodeling of central nervous system synapses. NLGN4X also interacts with discs, large (Drosophila) homolog 4 (DLG4). Defects in NLGN4X have been associated with autism and Asperger syndrome.
Nemo-like kinase contains 1 protein kinase domain and belongs to the protein kinase superfamily, CMGC Ser/Thr protein kinase family and MAP kinase subfamily. It also contains a TQE activation loop motif in which autophosphorylation of the threonine residue (Thr-298) is sufficient for kinase activation. As a serine/threonine-protein kinase, nemo-like kinase regulates a number of transcription factors with key roles in cell fate determination. It is a positive effector of the non-canonical Wnt signaling pathway, acting downstream of WNT5A, MAP3K7/TAK1 and HIPK2. Activation of this pathway causes binding to and phosphorylation of the histone methyltransferase SETDB1. The NLK-SETDB1 complex subsequently interacts with PPARG, leading to methylation of PPARG target promoters at histone H3K9 and transcriptional silencing. The resulting loss of PPARG target gene transcription inhibits adipogenesis and promotes osteoblastogenesis in mesenchymal stem cells (MSCs). Nemo-like kinase also is a negative regulator of the canonical Wnt/beta-catenin signaling pathway.
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