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NCR2 (natural cytotoxicity triggering receptor 2)

Written2013-06Nathan Horton, Kelly Bowen, Porunelloor Mathew
Department of Molecular Biology, Immunology, Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth Texas 76107, USA

(Note : for Links provided by Atlas : click)


Alias (NCBI)CD336
HGNC (Hugo) NCR2
HGNC Alias symbNK-p44
HGNC Previous nameLY95
HGNC Previous namelymphocyte antigen 95 (activating NK-receptor; NK-p44)
LocusID (NCBI) 9436
Atlas_Id 46140
Location 6p21.1  [Link to chromosome band 6p21]
Location_base_pair Starts at 41335608 and ends at 41350889 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping NCR2.png]
Local_order NKp44 is centromeric to the Major Histocompatibility Complex on Chromosome 6 in a cluster of single immunoglobulin variable domain receptors. NKp44 is centromeric by 49071 bp to triggering receptor expressed on myeloid cells (Trem-1), located on the negative strand, and telomeric to forkhead box p4 by 195539 bp.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note NKp44 is a transmembrane glycoprotein of the Immunoglobulin (Ig) superfamily expressed on the surface of IL-2 and IL-15 activated Natural Killer (NK) cells (Cantoni et al., 1999; de Rham et al., 2007; Rosental et al., 2011; Horton et al., 2013). NKp44, NKp30, and NKp46 make up the Natural Cytotoxicity receptors of the NK cell and cooperate with each other for optimal recognition and elimination of target cells (Augugliaro et al., 2003). NKp44 can either activate or inhibit NK cell effector function through recognition of separate ligands. NKp44 recognition of its unknown activating ligand facilitates signalling through Dap 12, resulting in release of cytotoxic agents, Tumor Necrosis Factor-α, and IFN-γ (Vitale et al., 1998). Recognition of cell surface Proliferating Cell Nuclear Antigen (PCNA) colocalizing with HLA I on the cell surface inhibits NK cell cytotoxicity and IFN-γ release (Rosental et al., 2011; Horton et al., 2013). NKp44 expression is inhibited by IL-21 (de Rham et al., 2007).


Note NKp44 is located on chromosome 6, centromeric to the Major Histocompatibility Complex. It is located in a cluster of single immunoglobulin variable domain receptors including Trem-1 and Trem-2 (Allcock et al., 2003).
  Three splice variants of NKp44. NKp44 is encoded on 5 exons (NM_004828.3). One splice variant contains an additional exon (NM_001199510.1), adding 35 amino acids resulting in a shift in the reading frame, truncating the cytoplasmic tail by 18 amino acids (Allcock et al., 2003). A second splice variant (NM_001199509.1) adds 12 amino acids, but maintains the reading frame with a 36 base pair extension on the 5' side of exon 4 (Allcock et al., 2003).
Description NKp44 gene spans 15098 bases located on positive strand of chromosome 6 from 41303528 to 41318625 bp. NKp44 is centromeric to Trem-1, with its leader sequence nearest to Trem-1 on the telomeric side and its cytoplasmic domain encoded towards the centromere (Allcock et al., 2003). NKp44 is encoded in 5 exons with one splice variant containing an extra exon (NM_001199510.1), adding 35 amino acids (Allcock et al., 2003). This addition alters the reading frame which truncates the cytoplasmic tail by 18 amino acids (Allcock et al., 2003). A second splice variant (NM_001199509.1) with an extra exon contains a 36 base pair extension of exon 4 on the 5' side, adding 12 amino acids, but maintaining the reading frame (Allcock et al., 2003).
Transcription There are three transcript variants of NKp44. Isoform 1 (NM_004828.3) encodes the longest isoform. Isoform 2 (NM_001199509.1) encodes a frame shift due to an extra in-frame segment and an additional exon compared to isoform 1. This results in an additional internal segment and a shorter C-terminus. Isoform 3 (NM001199510.1) has an additional exon with a shorter C-terminus similar to isoform 2.


Note NKp44 is a type I transmembrane protein belonging to the Ig Superfamily (Vitale et al., 1998; Cantoni et al., 1999; Cantoni et al., 2003). Surface expression of the receptor and signalling physically requires the transmembrane accessory protein DAP12 which bears Immunoreceptor Tyrosine Activation Motifs (Cantoni et al., 1999). NKp44 activates NK cells through DAP12 linked directly to Lysine 183 in the transmembrane domain (Campbell et al., 2004). NKp44 inhibits NK cells through a tyrosine-based inhibitory motif located in the cytoplasmic tail of the receptor (Rosental et al., 2011).
Description NKp44 has a molecular weight of 44 kDa and consists of a 169 amino acid extracellular domain followed by 23 and 63 amino acid sequences in the transmembrane and cytoplasmic tail domains respectively (Cantoni et al., 1999; Cantoni et al., 2003). A 55 amino acid domain connects the extracellular Ig domain to the transmembrane segment and has 13 predicted O-glycosylation sites and a single N-glycosylation site (Cantoni et al., 1999; Cantoni et al., 2003). Crystallography of the receptor demonstrates a surface groove made by two facing β hairpin loops extending from the Ig fold core stabilized by a disulfide bridge between Cystine 37 and Cystine 45 (Cantoni et al., 2003). The Ig domain contains an arrangement of positively charged residues at the groove surface, suggesting NKp44 ligands are anionic (Cantoni et al., 2003). The groove appears wide enough to host a sialic acid or an elongated branched ligand. The cytoplasmic tail of NKp44 also contains a tyrosine sequence resembling a tyrosine-based inhibitory motif (Cantoni et al., 1999; Campbell et al., 2004). This motif is functional and inhibits the release of cytotoxic agents and IFN-γ (Rosental et al., 2011).
Expression NKp44 is expressed on IL-2 and IL-15 activated NK Cells and NK cells in the decidua (Cantoni et al., 1999; de Rham et al., 2007; Manaster and Mandelboim, 2010). The receptor is also expressed on isolated polyclonal γδ T cells when cultured for 2 weeks in IL-15 and IL-2 (Cantoni et al., 1999; von Lilienfeld-Toal et al., 2006; Hudspeth et al., 2013). Natural Interferon-producing cells located in the T-cell zone in lymph nodes draining a site of viral infection are reported to express NKp44, believed to be induced by IL-3 from local memory CD8 T cells (Fuchs et al., 2005). NKp44 is also induced in TCR αβ intestinal intraepithelial lymphocytes by IL-15 (Meresse et al., 2004). Cytolytic T cells isolated from cord blood express NKp44 when induced with IL-2 or IL-15 (Tang et al., 2008). Finally NKp44 is expressed on a subset of cells located in human tonsils, similar to lymphoid tissue induce cells, which produce IL-22 and express Rorγt (Fuchs et al., 2005; Cella et al., 2009).
Localisation NKp44 is a type I transmembrane protein expressed on the surface of IL-2 activated NK cells and induced in γδ T cells by IL-15 and IL-2 (Cantoni et al., 1999; von Lilienfeld-Toal et al., 2006; Hudspeth et al., 2013). Expression is also reported on the cell surface of natural interferon-producing cells exposed to IL-3 (Fuchs et al., 2005).
Function NKp44 may functions as either an activating or inhibitory receptor on the surface of the NK cell. The identities of activating ligands are currently unknown, but bind NKp44 to induce activating signals through Dap12 (Vitale et al., 1998; Cantoni et al., 1999; Campbell et al., 2004). NKp44 inhibits NK cell function through recognition of cell surface exosomal PCNA which colocalizes with HLA I (Rosental et al., 2011; Horton et al., 2013).
Homology - NCR 2 Natural Cytotoxicity Trigger Receptor 2 [Pan troglodytes] NC_006473.3
- NCR 2 Natural Cytotoxicity Trigger Receptor 2 [Macaca mulatta] NC_007861.1
- NCR 2 Natural Cytotoxicity Trigger Receptor 2 [Canis lupus familiaris] NC_006594.3


Note None identified.

Implicated in

Entity Various cancers
Note NKp44 is implicated in recognition of numerous types of cancer (neuralblastoma, choriocarcinoma, pancreatic, breast, lung adenocarcinoma, colon, cervix, hepatocellular carcinoma, Burkitt lymphoma, diffuse B cell lymphoma, prostate) (Sivori et al., 2000a; Sivori et al., 2000b; Byrd et al., 2007; Rosental et al., 2011; Horton et al., 2013). Ligands for NKp44 appear to be cell cycle regulated, with down regulation of expression during mitosis (Byrd et al., 2007). Recognition of tumor cells is partially mediated through charged based binding of NKp44 with heparin sulfate proteoglycans (HSPG) on the surface of tumor cells (Hershkovitz et al., 2007). Specifically, the 2-O-sulfation of iduronic acid and N-acetylation of glucosamine on HSPGs are important for interaction with NKp44 (Hecht et al., 2009). Glycans containing α2,6-N¬-acetylneuraminic acid are also recognized on the surface of cancer cells by NKp44 (Ito et al., 2012). HSPGs are believed to be a coligand for NKp44 and the other NCRs, potentially facilitating binding with other cellular ligands. Recognition of HSPG only evokes IFN-γ release by NK cells, not cellular cytotoxicity (Hershkovitz et al., 2007).
Entity Tumor escape of immunosurveillance
Note Tumors employ numerous mechanisms to avoid killing by NK cells. By engaging NKp44, as well as the other NCRs, tumors can induce NK cell death via up regulation of Fas Ligand in the NK cell, inducing Fas mediated apoptosis (Poggi et al., 2005). NKp44 surface expression can be down regulated by soluble MHC Class I chain-related molecules shed by colorectal tumors or by indoleamine 2,3-dioxygenase and prostaglandin E2 released by melanoma cells (Doubrovina et al., 2003; Pietra et al., 2012). Mesenchymal stem cells also release indoleamine 2,3-dioxygenase and prostaglandin E2 which inhibit NKp44 induction in the tumor microenvironment, but may also be harnessed as a therapeutic approach to inhibit Graft-versus-host or autoimmune disease (Spaggiari et al., 2008). Tumors may also down regulate NKp44 ligand expression to escape NK cell killing, as is the case with Acute Myeloid Leukemia (AML) (Nowbakht et al., 2005). In the case of normal myelonocytic differentiation of bone marrow cells, a ligand for NKp44 is expressed upon loss of the CD34 hematopoietic marker and acquisition of CD33 and CD14 myeloid markers (Nowbakht et al., 2005). Ligand expression if further increased by the presence of IFN-γ (Nowbakht et al., 2005). Yet in AML, ligand expression is absent, possibly contributing to disease manifestation. Finally, tumor cells may also induce expression of exosomal PCNA when physically contacted by NKp44 expressing NK cells to inhibit NK cell effector function (Rosental et al., 2011).
Entity Viral infection
Note NKp44 recognizes α2,6-N¬-acetylneuraminic acid of hemagglutinin of Influenza and Sendai viruses and hemagglutinin-neuraminidase of the Newcastle disease virus, requiring sialyation of the receptor (Arnon et al., 2001; Jarahian et al., 2009; Ito et al., 2012). Binding of NKp44 to hemagglutinin enables lysis of viral infected cells. Specifically, NKp44 recognizes hemagglutinins from H5-type influenza virus strains (Ho et al., 2008). Two flaviviruses, Dengue and West Nile, are directly recognized by NKp44. Envelope proteins of these viruses, in particular domain III of West Nile, directly bind to NKp44, increasing lysis of infected cells and NK cell IFN-γ release (Hershkovitz et al., 2009). NKp44 is also implicated in recognizing a ligand expressed on cells infected with Vaccina virus (Chisholm and Reyburn, 2006). Viruses have also evolved immune escape mechanisms by down regulating expression of the ligand for NKp44. In the case of Kaposi's sarcoma-associated herpes virus, the extracellular ligand expression is reduced during de novo infection. Interestingly, during lytic infection, only surface levels of the NKp44 ligand are reduced as overall cellular levels are unchanged, indicating a defect in cellular trafficking (Madrid and Ganem, 2012). Also, while the NKp44 ligand is typically located outside of the nucleus, during lytic infection the ligand is found localizing to the nucleus (Madrid and Ganem, 2012). This localization is concurrent with a burst of lytic gene expression, mainly consisting of immune related genes (Madrid and Ganem, 2012).
Entity HIV
Note A hallmark of HIV infection is the progressive depletion of CD4+ T cells via destruction of both uninfected CD4+ T cells and HIV-infected CD4+ T cells. In regards to NK cells, HIV modulates both the expression of NK cell receptors and their ligands. NKp44 is no exception as it is expressed at a lower surface density on in vitro activated NK cells from HIV-1 patients compared to healthy controls, resulting in decreased killing of various tumor target cells (De Maria et al., 2003; Mavilio et al., 2003; Fogli et al., 2004). HIV also modulates NK cell receptor ligand expression. NKp44 cellular ligand (NKp44L) is expressed on uninfected CD4+ T cells during an HIV infection, correlating with the loss of CD4+ T cells and increase of viral load (Vieillard et al., 2005). NKp44L is only expressed in high amounts on uninfected CD4+ T cells and is not responsible for inducing NK lysis of HIV-infected cells (Ward et al., 2007). To avoid NK killing of HIV infected CD4+ T cells, the Nef protein of HIV-1 retains NKp44L intracellularly, preventing cell surface expression and interaction with NKp44 (Fausther-Bovendo et al., 2009). Studies by Vieillard et al. have shown a highly conserved 3S peptide motif of the HIV-1 gp41 protein is involved in the induction of NKp44L on the surface of uninfected CD4+ T cells. An envelope protein of the HIV virus, gp41 is vital for viral entry into target cells (Vieillard et al., 2005). The 3S peptide of gp41 binds to its receptor gC1qR, a receptor for the globular domain of complement component 1q, on CD4+ T cells (Fausther-Bovendo et al., 2010). Binding of the 3S motif to this receptor activates a signaling cascade involving PI3K, NADPH-oxidase, Rho-A, and TC10 (Fausther-Bovendo et al., 2010). NKp44L is translocated from the cytoplasm to the plasma membrane and is expressed on the cell surface, where it can bind to NKp44 of activated NK cells. NKp44L+ expressing CD4+ T cells are more susceptible to lysis by activated NK cells (Vieillard et al., 2005). Understanding the role of NKp44L during HIV infection could help identify new therapeutic strategies to prevent the progressive loss of uninfected CD4+ T cells. Possible therapeutic strategies are to inhibit the expression of NKp44L by using an anti-gp41 Ab or an anti-gC1qR Ab to block the 3S motif and gC1qR interaction (Vieillard et al., 2005; Fausther-Bovendo et al., 2010). Anti-3S immunization has also proven efficacious in preliminary studies in macaques (Vieillard et al., 2008).
Entity Microbial infection
Note Nkp44 is reported to directly bind to the surface of Mycobacterium and other related genera. After in vitro stimulation with Mycobacterium bovis bacillus Calmette-Guérin (BCG) for 3 to 4 days, CD56bright NK cells significantly increase NKp44 expression (Esin et al., 2008). The Mycobacterium genus, including the causative agent of tuberculosis, Mycobacterium tuberculosis, express a conserved NKp44 ligand while the mycobacterium related, Gram-positive Nocardia and Corynbacterium genera, also express a ligand (Esin et al., 2008; Esin et al., 2013). Interestingly, both Nocardia, Corynbacterium, and Mycobacterium genera express mycolic acids in their cell walls, which is lacking in other mycobacterium related species which do not express a ligand for NKp44 (Esin et al., 2008). Furthermore, the BCG NKp44 ligand was found to be resistant to trypsin degradation and stable at 80°C, indicating the ligand is most likely not a protein but a heat stable structural component of the cell wall (Esin et al., 2008). In a subsequent study, Esin et al. further proved NKp44 specifically binds mycolyl-arabinogalactan-peptidoglycan, mycolic acid, and arabinogalactan found in the cell wall of Mycobacterium tuberculosis to maintain NK cell activation (Esin et al., 2013). Finally, Pseudomonas aeruginosa also express a ligand for NKp44 (Esin et al., 2008).
Entity Formation of placenta
Note Decidual NK cells (dNK) make up 50-90% of lymphocytes in the uterine mucosa during pregnancy and constitutively express NKp44 (Kopcow et al., 2005; Hanna et al., 2006; Vacca et al., 2008). In close contact with fetal extravillous trophoblasts cells invading the maternal decidua, dNK cells exhibit reduced cytotoxicity but crucially produce Interleukin-8, Interferon-inducible protein 10, Vascular Endothelial Growth Factor (VEGF), and Placental Growth Factor (PGF) in response to NKp44 triggering (Hanna et al., 2006; Vacca et al., 2008). Trophoblast cells and maternal stromal cells of the decidua both express unidentified NKp44 ligands (Hanna et al., 2006; Vacca et al., 2008). This ligand may be PCNA as the protein is over expressed in trophoblast cells during the first trimester (Korgun et al., 2006). As an inhibitory ligand for NKp44, extracellular PCNA expression on trophoblast cells would help explain the diminished ability of dNK cells to lyse trophoblasts despite low levels of classical HLA I expression (Vacca et al., 2008). Invasion of trophoblast into decidua facilitates proper placentation and NK cells help govern how far trophoblasts infiltrate (Moffett and Loke, 2006). dNK cells also help reorganize the spiral arteries to facilitate appropriate blood transfer between the mother and fetus at the placenta (Moffett and Loke, 2006; Vacca et al., 2008). Alterations in dNK cells and invasion of fetal trophoblast cells are implicated in pregnancy complications, such as pre-eclampsia and tubal pregnancies (Moffett and Loke, 2006). Since fetal trophoblast and maternal decidual cells express a NKp44 ligand, this receptor constitutively expressed on dNK cell plays a crucial role in proper development of the placenta in pregnancy that requires further study.
Entity Spontaneous abortion
Note NKp44 expression is increased on CD56brightCD16- dNK cells in patients with spontaneous abortion, resulting in increased cytolytic activity of these NK cells (Zhang et al., 2008).
Entity Crohn's Disease and ankylosing spondylitis
Note NKp44+ NK cells (CD3-CD56+NKp44+NKp46-RORChighCD122-CD127+) in the intestinal lamina propria are significantly reduced in inflamed mucosa of patients with Crohn's Disease (CD) while IFN-γ producing NKp46+ NK cells (CD3-CD56+NKp44-NKp46+RORCdullCD122+CD127-) are dramatically increased (Takayama et al., 2010). IL-22 is produced by NKp44+ NK cells, which is protective in the onset of murine colitis, and possibly implicated in human colitis. Thus the imbalance of the NKp44+/NKp46+ NK cell axis in the intestinal lamina propria may play a role in colitis onset (Takayama et al., 2010). Contrary to CD, NKp44+ NK cells are increased in the inflamed ileum of patients with Ankylosing Spondylitis (AS) (Ciccia et al., 2012). AS Patients over express IL-23 in the intestines which modulates IL-22 production by NKp44+IL-22+ NK cells (Ciccia et al., 2012). IL-22 then promotes mucosal wound healing through increased mucin production by goblet cells.


The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44.
Allcock RJ, Barrow AD, Forbes S, Beck S, Trowsdale J.
Eur J Immunol. 2003 Feb;33(2):567-77.
PMID 12645956
Recognition of viral hemagglutinins by NKp44 but not by NKp30.
Arnon TI, Lev M, Katz G, Chernobrov Y, Porgador A, Mandelboim O.
Eur J Immunol. 2001 Sep;31(9):2680-9.
PMID 11536166
Selective cross-talk among natural cytotoxicity receptors in human natural killer cells.
Augugliaro R, Parolini S, Castriconi R, Marcenaro E, Cantoni C, Nanni M, Moretta L, Moretta A, Bottino C.
Eur J Immunol. 2003 May;33(5):1235-41.
PMID 12731048
Expression analysis of the ligands for the Natural Killer cell receptors NKp30 and NKp44.
Byrd A, Hoffmann SC, Jarahian M, Momburg F, Watzl C.
PLoS One. 2007 Dec 19;2(12):e1339.
PMID 18092004
NKp44 triggers NK cell activation through DAP12 association that is not influenced by a putative cytoplasmic inhibitory sequence.
Campbell KS, Yusa S, Kikuchi-Maki A, Catina TL.
J Immunol. 2004 Jan 15;172(2):899-906.
PMID 14707061
NKp44, a triggering receptor involved in tumor cell lysis by activated human natural killer cells, is a novel member of the immunoglobulin superfamily.
Cantoni C, Bottino C, Vitale M, Pessino A, Augugliaro R, Malaspina A, Parolini S, Moretta L, Moretta A, Biassoni R.
J Exp Med. 1999 Mar 1;189(5):787-96.
PMID 10049942
The three-dimensional structure of the human NK cell receptor NKp44, a triggering partner in natural cytotoxicity.
Cantoni C, Ponassi M, Biassoni R, Conte R, Spallarossa A, Moretta A, Moretta L, Bolognesi M, Bordo D.
Structure. 2003 Jun;11(6):725-34.
PMID 12791260
A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity.
Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JK, Doherty JM, Mills JC, Colonna M.
Nature. 2009 Feb 5;457(7230):722-5. doi: 10.1038/nature07537. Epub 2008 Nov 2.
PMID 18978771
Recognition of vaccinia virus-infected cells by human natural killer cells depends on natural cytotoxicity receptors.
Chisholm SE, Reyburn HT.
J Virol. 2006 Mar;80(5):2225-33.
PMID 16474130
Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis.
Ciccia F, Accardo-Palumbo A, Alessandro R, Rizzo A, Principe S, Peralta S, Raiata F, Giardina A, De Leo G, Triolo G.
Arthritis Rheum. 2012 Jun;64(6):1869-78. doi: 10.1002/art.34355. Epub 2011 Dec 27.
PMID 22213179
The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44).
De Maria A, Fogli M, Costa P, Murdaca G, Puppo F, Mavilio D, Moretta A, Moretta L.
Eur J Immunol. 2003 Sep;33(9):2410-8.
PMID 12938217
Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma.
Doubrovina ES, Doubrovin MM, Vider E, Sisson RB, O'Reilly RJ, Dupont B, Vyas YM.
J Immunol. 2003 Dec 15;171(12):6891-9.
PMID 14662896
Direct binding of human NK cell natural cytotoxicity receptor NKp44 to the surfaces of mycobacteria and other bacteria.
Esin S, Batoni G, Counoupas C, Stringaro A, Brancatisano FL, Colone M, Maisetta G, Florio W, Arancia G, Campa M.
Infect Immun. 2008 Apr;76(4):1719-27. doi: 10.1128/IAI.00870-07. Epub 2008 Jan 22.
PMID 18212080
Interaction of Mycobacterium tuberculosis cell wall components with the human natural killer cell receptors NKp44 and Toll-like receptor 2.
Esin S, Counoupas C, Aulicino A, Brancatisano FL, Maisetta G, Bottai D, Di Luca M, Florio W, Campa M, Batoni G.
Scand J Immunol. 2013 Jun;77(6):460-9. doi: 10.1111/sji.12052.
PMID 23578092
HIV gp41 engages gC1qR on CD4+ T cells to induce the expression of an NK ligand through the PIP3/H2O2 pathway.
Fausther-Bovendo H, Vieillard V, Sagan S, Bismuth G, Debre P.
PLoS Pathog. 2010 Jul 1;6:e1000975. doi: 10.1371/journal.ppat.1000975.
PMID 20617170
Significant NK cell activation associated with decreased cytolytic function in peripheral blood of HIV-1-infected patients.
Fogli M, Costa P, Murdaca G, Setti M, Mingari MC, Moretta L, Moretta A, De Maria A.
Eur J Immunol. 2004 Aug;34(8):2313-21.
PMID 15259029
Paradoxic inhibition of human natural interferon-producing cells by the activating receptor NKp44.
Fuchs A, Cella M, Kondo T, Colonna M.
Blood. 2005 Sep 15;106(6):2076-82. Epub 2005 Jun 7.
PMID 15941912
Decidual NK cells regulate key developmental processes at the human fetal-maternal interface.
Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, Prus D, Cohen-Daniel L, Arnon TI, Manaster I, Gazit R, Yutkin V, Benharroch D, Porgador A, Keshet E, Yagel S, Mandelboim O.
Nat Med. 2006 Sep;12(9):1065-74. Epub 2006 Aug 6.
PMID 16892062
Natural cytotoxicity receptors NKp30, NKp44 and NKp46 bind to different heparan sulfate/heparin sequences.
Hecht ML, Rosental B, Horlacher T, Hershkovitz O, De Paz JL, Noti C, Schauer S, Porgador A, Seeberger PH.
J Proteome Res. 2009 Feb;8(2):712-20. doi: 10.1021/pr800747c.
PMID 19196184
NKp44 receptor mediates interaction of the envelope glycoproteins from the West Nile and dengue viruses with NK cells.
Hershkovitz O, Rosental B, Rosenberg LA, Navarro-Sanchez ME, Jivov S, Zilka A, Gershoni-Yahalom O, Brient-Litzler E, Bedouelle H, Ho JW, Campbell KS, Rager-Zisman B, Despres P, Porgador A.
J Immunol. 2009 Aug 15;183(4):2610-21. doi: 10.4049/jimmunol.0802806. Epub 2009 Jul 27.
PMID 19635919
H5-type influenza virus hemagglutinin is functionally recognized by the natural killer-activating receptor NKp44.
Ho JW, Hershkovitz O, Peiris M, Zilka A, Bar-Ilan A, Nal B, Chu K, Kudelko M, Kam YW, Achdout H, Mandelboim M, Altmeyer R, Mandelboim O, Bruzzone R, Porgador A.
J Virol. 2008 Feb;82(4):2028-32. Epub 2007 Dec 12.
PMID 18077718
Novel interaction between proliferating cell nuclear antigen and HLA I on the surface of tumor cells inhibits NK cell function through NKp44.
Horton NC, Mathew SO, Mathew PA.
PLoS One. 2013;8(3):e59552. doi: 10.1371/journal.pone.0059552. Epub 2013 Mar 19.
PMID 23527218
Natural cytotoxicity receptors: broader expression patterns and functions in innate and adaptive immune cells.
Hudspeth K, Silva-Santos B, Mavilio D.
Front Immunol. 2013 Mar 20;4:69. doi: 10.3389/fimmu.2013.00069. eCollection 2013.
PMID 23518691
Unlike natural killer (NK) p30, natural cytotoxicity receptor NKp44 binds to multimeric ?2,3-NeuNAc-containing N-glycans.
Ito K, Higai K, Shinoda C, Sakurai M, Yanai K, Azuma Y, Matsumoto K.
Biol Pharm Bull. 2012;35(4):594-600.
PMID 22466566
Activation of natural killer cells by newcastle disease virus hemagglutinin-neuraminidase.
Jarahian M, Watzl C, Fournier P, Arnold A, Djandji D, Zahedi S, Cerwenka A, Paschen A, Schirrmacher V, Momburg F.
J Virol. 2009 Aug;83(16):8108-21. doi: 10.1128/JVI.00211-09. Epub 2009 Jun 10.
PMID 19515783
Human decidual NK cells form immature activating synapses and are not cytotoxic.
Kopcow HD, Allan DS, Chen X, Rybalov B, Andzelm MM, Ge B, Strominger JL.
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15563-8. Epub 2005 Oct 17.
PMID 16230631
Location of cell cycle regulators cyclin B1, cyclin A, PCNA, Ki67 and cell cycle inhibitors p21, p27 and p57 in human first trimester placenta and deciduas.
Korgun ET, Celik-Ozenci C, Acar N, Cayli S, Desoye G, Demir R.
Histochem Cell Biol. 2006 Jun;125(6):615-24. Epub 2006 Feb 21.
PMID 16491347
Kaposi's sarcoma-associated herpesvirus ORF54/dUTPase downregulates a ligand for the NK activating receptor NKp44.
Madrid AS, Ganem D.
J Virol. 2012 Aug;86(16):8693-704. doi: 10.1128/JVI.00252-12. Epub 2012 Jun 6.
PMID 22674989
The unique properties of uterine NK cells.
Manaster I, Mandelboim O.
Am J Reprod Immunol. 2010 Jun;63(6):434-44. doi: 10.1111/j.1600-0897.2009.00794.x. Epub 2010 Jan 4. (REVIEW)
PMID 20055791
Natural killer cells in HIV-1 infection: dichotomous effects of viremia on inhibitory and activating receptors and their functional correlates.
Mavilio D, Benjamin J, Daucher M, Lombardo G, Kottilil S, Planta MA, Marcenaro E, Bottino C, Moretta L, Moretta A, Fauci AS.
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15011-6. Epub 2003 Nov 25.
PMID 14645713
Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.
Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Lanier LL, Groh V, Spies T, Ebert EC, Green PH, Jabri B.
Immunity. 2004 Sep;21(3):357-66.
PMID 15357947
Immunology of placentation in eutherian mammals.
Moffett A, Loke C.
Nat Rev Immunol. 2006 Aug;6(8):584-94. (REVIEW)
PMID 16868549
Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias.
Nowbakht P, Ionescu MC, Rohner A, Kalberer CP, Rossy E, Mori L, Cosman D, De Libero G, Wodnar-Filipowicz A.
Blood. 2005 May 1;105(9):3615-22. Epub 2005 Jan 18.
PMID 15657183
Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity.
Pietra G, Manzini C, Rivara S, Vitale M, Cantoni C, Petretto A, Balsamo M, Conte R, Benelli R, Minghelli S, Solari N, Gualco M, Queirolo P, Moretta L, Mingari MC.
Cancer Res. 2012 Mar 15;72(6):1407-15. doi: 10.1158/0008-5472.CAN-11-2544. Epub 2012 Jan 18.
PMID 22258454
Tumor-induced apoptosis of human IL-2-activated NK cells: role of natural cytotoxicity receptors.
Poggi A, Massaro AM, Negrini S, Contini P, Zocchi MR.
J Immunol. 2005 Mar 1;174(5):2653-60.
PMID 15728472
Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44.
Rosental B, Brusilovsky M, Hadad U, Oz D, Appel MY, Afergan F, Yossef R, Rosenberg LA, Aharoni A, Cerwenka A, Campbell KS, Braiman A, Porgador A.
J Immunol. 2011 Dec 1;187(11):5693-702. doi: 10.4049/jimmunol.1102267. Epub 2011 Oct 21.
PMID 22021614
Triggering receptors involved in natural killer cell-mediated cytotoxicity against choriocarcinoma cell lines.
Sivori S, Parolini S, Marcenaro E, Millo R, Bottino C, Moretta A.
Hum Immunol. 2000b Nov;61(11):1055-8.
PMID 11137207
Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2.
Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L.
Blood. 2008 Feb 1;111(3):1327-33. Epub 2007 Oct 19.
PMID 17951526
Imbalance of NKp44(+)NKp46(-) and NKp44(-)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn's disease.
Takayama T, Kamada N, Chinen H, Okamoto S, Kitazume MT, Chang J, Matuzaki Y, Suzuki S, Sugita A, Koganei K, Hisamatsu T, Kanai T, Hibi T.
Gastroenterology. 2010 Sep;139(3):882-92, 892.e1-3. doi: 10.1053/j.gastro.2010.05.040. Epub 2010 Jun 1.
PMID 20638936
Umbilical cord blood T cells express multiple natural cytotoxicity receptors after IL-15 stimulation, but only NKp30 is functional.
Tang Q, Grzywacz B, Wang H, Kataria N, Cao Q, Wagner JE, Blazar BR, Miller JS, Verneris MR.
J Immunol. 2008 Oct 1;181(7):4507-15.
PMID 18802053
Regulatory role of NKp44, NKp46, DNAM-1 and NKG2D receptors in the interaction between NK cells and trophoblast cells. Evidence for divergent functional profiles of decidual versus peripheral NK cells.
Vacca P, Cantoni C, Prato C, Fulcheri E, Moretta A, Moretta L, Mingari MC.
Int Immunol. 2008 Nov;20(11):1395-405. doi: 10.1093/intimm/dxn105. Epub 2008 Sep 23.
PMID 18815119
A vaccine strategy against AIDS: an HIV gp41 peptide immunization prevents NKp44L expression and CD4+ T cell depletion in SHIV-infected macaques.
Vieillard V, Le Grand R, Dausset J, Debre P.
Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2100-4. doi: 10.1073/pnas.0711629105. Epub 2008 Jan 30.
PMID 18234855
NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis.
Vitale M, Bottino C, Sivori S, Sanseverino L, Castriconi R, Marcenaro E, Augugliaro R, Moretta L, Moretta A.
J Exp Med. 1998 Jun 15;187(12):2065-72.
PMID 9625766
HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts.
Ward J, Bonaparte M, Sacks J, Guterman J, Fogli M, Mavilio D, Barker E.
Blood. 2007 Aug 15;110(4):1207-14. Epub 2007 May 18.
PMID 17513617
Expressions of natural cytotoxicity receptors and NKG2D on decidual natural killer cells in patients having spontaneous abortions.
Zhang Y, Zhao A, Wang X, Shi G, Jin H, Lin Q.
Fertil Steril. 2008 Nov;90(5):1931-7. Epub 2007 Nov 26.
PMID 18023431
The proinflammatory cytokines IL-2, IL-15 and IL-21 modulate the repertoire of mature human natural killer cell receptors.
de Rham C, Ferrari-Lacraz S, Jendly S, Schneiter G, Dayer JM, Villard J.
Arthritis Res Ther. 2007;9(6):R125.
PMID 18053164
Activated gammadelta T cells express the natural cytotoxicity receptor natural killer p 44 and show cytotoxic activity against myeloma cells.
von Lilienfeld-Toal M, Nattermann J, Feldmann G, Sievers E, Frank S, Strehl J, Schmidt-Wolf IG.
Clin Exp Immunol. 2006 Jun;144(3):528-33.
PMID 16734623


This paper should be referenced as such :
Horton, N ; Bowen, K ; Mathew, P
NCR2 (natural cytotoxicity triggering receptor 2)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(1):16-22.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)NCR2   6732
Entrez_Gene (NCBI)NCR2    natural cytotoxicity triggering receptor 2
AliasesCD336; LY95; NK-p44; NKP44; 
GeneCards (Weizmann)NCR2
Ensembl hg19 (Hinxton)ENSG00000096264 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000096264 [Gene_View]  ENSG00000096264 [Sequence]  chr6:41335608-41350889 [Contig_View]  NCR2 [Vega]
ICGC DataPortalENSG00000096264
TCGA cBioPortalNCR2
AceView (NCBI)NCR2
Genatlas (Paris)NCR2
SOURCE (Princeton)NCR2
Genetics Home Reference (NIH)NCR2
Genomic and cartography
GoldenPath hg38 (UCSC)NCR2  -     chr6:41335608-41350889 +  6p21.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)NCR2  -     6p21.1   [Description]    (hg19-Feb_2009)
GoldenPathNCR2 - 6p21.1 [CytoView hg19]  NCR2 - 6p21.1 [CytoView hg38]
Genome Data Viewer NCBINCR2 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AJ010099 AJ010100
RefSeq transcript (Entrez)NM_001199509 NM_001199510 NM_004828
Consensus coding sequences : CCDS (NCBI)NCR2
Gene ExpressionNCR2 [ NCBI-GEO ]   NCR2 [ EBI - ARRAY_EXPRESS ]   NCR2 [ SEEK ]   NCR2 [ MEM ]
Gene Expression Viewer (FireBrowse)NCR2 [ Firebrowse - Broad ]
GenevisibleExpression of NCR2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9436
GTEX Portal (Tissue expression)NCR2
Human Protein AtlasENSG00000096264-NCR2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO95944   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO95944  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO95944
Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)   
Domains : Interpro (EBI)Ig-like_dom    Ig-like_dom_sf    Ig-like_fold    Ig_sub    Ig_V-set   
Domain families : Pfam (Sanger)V-set (PF07686)   
Domain families : Pfam (NCBI)pfam07686   
Domain families : Smart (EMBL)IG (SM00409)  
Conserved Domain (NCBI)NCR2
PDB Europe1HKF   
Structural Biology KnowledgeBase1HKF   
SCOP (Structural Classification of Proteins)1HKF   
CATH (Classification of proteins structures)1HKF   
AlphaFold pdb e-kbO95944   
Human Protein Atlas [tissue]ENSG00000096264-NCR2 [tissue]
Protein Interaction databases
IntAct (EBI)O95944
Ontologies - Pathways
Ontology : AmiGOtransmembrane signaling receptor activity  protein binding  plasma membrane  integral component of plasma membrane  cellular defense response  signal transduction  cell surface  signaling receptor activity  innate immune response  regulation of immune response  
Ontology : EGO-EBItransmembrane signaling receptor activity  protein binding  plasma membrane  integral component of plasma membrane  cellular defense response  signal transduction  cell surface  signaling receptor activity  innate immune response  regulation of immune response  
Pathways : KEGGNatural killer cell mediated cytotoxicity   
REACTOMEO95944 [protein]
REACTOME PathwaysR-HSA-2172127 [pathway]   
NDEx NetworkNCR2
Atlas of Cancer Signalling NetworkNCR2
Wikipedia pathwaysNCR2
Orthology - Evolution
GeneTree (enSembl)ENSG00000096264
Phylogenetic Trees/Animal Genes : TreeFamNCR2
Homologs : HomoloGeneNCR2
Homology/Alignments : Family Browser (UCSC)NCR2
Gene fusions - Rearrangements
Fusion : QuiverNCR2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNCR2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NCR2
Exome Variant ServerNCR2
GNOMAD BrowserENSG00000096264
Varsome BrowserNCR2
ACMGNCR2 variants
Genomic Variants (DGV)NCR2 [DGVbeta]
DECIPHERNCR2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisNCR2 
ICGC Data PortalNCR2 
TCGA Data PortalNCR2 
Broad Tumor PortalNCR2
OASIS PortalNCR2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNCR2  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DNCR2
Mutations and Diseases : HGMDNCR2
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)NCR2
DoCM (Curated mutations)NCR2
CIViC (Clinical Interpretations of Variants in Cancer)NCR2
NCG (London)NCR2
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry NCR2
NextProtO95944 [Medical]
Target ValidationNCR2
Huge Navigator NCR2 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDNCR2
Pharm GKB GenePA30496
Clinical trialNCR2
DataMed IndexNCR2
PubMed52 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:23:29 CEST 2021

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