NKp44 and NKp30 splice variant profiles in decidua and tumor tissues: a comparative viewpoint

Shemesh, Avishai; Kugel, Aleksandra; Steiner, Naama; Yezersky, Michal; Tirosh, Dan; Edri, Avishay; Teltsh, Omri; Rosental, Benyamin; Sheiner, Eyal; Rubin, Eitan; Campbell, Kerry S.; Porgador, Angel

doi:10.18632/oncotarget.12292

Cited by 14 publications

(19 citation statements)

References 45 publications

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“…Shemesh et al also found that NKp44-2 and NKp44-3 isoforms predominated in decidual tissue obtained from the majority of first trimester spontaneous abortions, while a NKp44-1-dominant (inhibitory) profile was found in dNK cells from most elective abortions or term deliveries (healthy pregnancies), which is consistent with the inhibitory function of dNK cells in the study by Siewiera et al (95). …”

Section: Splice Variants Of Ncrs Resulting In Distinct Receptor Isoformssupporting

confidence: 77%

“…Moreover, a subset of GIST patients with predominant expression of the NKp30c isoform and a distinct haplotype involving two SNPs in the ncr3 gene were found to be associated with particularly poor survival (94). For GI carcinomas and variety of other cancers, we observed that both cancerous and matched normal tissues manifested balanced NKp30c inhibitory and NKp30a/b activation profiles; yet, we found skewed NKp30 splice variant profiles in about 50% of a variety of tumor tissues compared to their matched normal tissues (95). …”

Section: Splice Variants Of Ncrs Resulting In Distinct Receptor Isoformsmentioning

confidence: 79%

“…The same group found higher incidence of NKp44 mRNA in various solid tumor tissues, as compared to surrounding normal tissues (95). Those tumor samples that expressed NKp44 mRNA were found to consist of predominantly NKp44-1 isoform.…”

Section: Splice Variants Of Ncrs Resulting In Distinct Receptor Isoformsmentioning

confidence: 92%

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Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

et al. 2017

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The natural cytotoxicity receptor (NCR) family is constituted by NKp46, NKp44, and NKp30 in humans, which are expressed mainly on natural killer (NK) cells and are encoded by the ncr1, ncr2, and ncr3 genes, respectively. NCRs have classically been defined as activating receptors that trigger cytotoxicity and cytokine responses by NK cells upon engaging with ligands on tumor cells. Several new findings, however, have challenged this model and identified alternative mechanisms regulating the function of NCRs. Recent reports indicate that ligand matters, since the interaction of NKp44 with distinct ligands on target cells can either activate or inhibit NK cells. Also, the NCRs have been found to interact with distinct specificities to various heparan sulfate glycosaminoglycans, which are complex polysaccharides found in extracellular matrix or on cell surface heparan sulfate proteoglycans (HSPGs). The NCRs can engage with HSPGs in trans as a co-ligand on the target cells or in cis on the NK cell surface to regulate receptor–ligand interactions and NK cell activation. A number of splice variants of ncr2 and ncr3 have also been identified, and a predominant expression of certain variants results in inhibitory signaling through NKp44 and NKp30. Several recent studies have found that the selective expression of some of these inhibitory splice variants can significantly influence outcome in the contexts of cancer, infection, and pregnancy. These findings establish that NCR functions are more diverse than originally thought, and better understanding of their splice variant expression profiles and ligand interactions are needed to establish their functional regulation in the context of human health.

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Section: Splice Variants Of Ncrs Resulting In Distinct Receptor Isoformssupporting

confidence: 77%

Section: Splice Variants Of Ncrs Resulting In Distinct Receptor Isoformsmentioning

confidence: 79%

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Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

et al. 2017

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“…1). NKp44 (NCR2) is a 44 kDa protein, consisting of a single extracellular V-type Ig (IgV) domain (44)(45)(46), followed by a long stalk region and a hydrophobic transmembrane domain. The latter contains a charged lysine residue that leads to association with DAP12 adaptor with ITAM (47) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Activating NK- receptors, homing selectins and inhibitory Siglecs recognize EBOLA-GP and HPV-L1NK

Jarahian

Marstaller

Wurmbäck

et al. 2020

Preprint

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The Ebola virus glycoprotein (EBOV)-GP is extensively glycosylated. Its expression induces a physical alteration of surface adhesion molecules, which causes cell rounding and detachment of the infected cells. This phenomenon likely plays a crucial role in viral pathogenicity. In this study, we show that such morphological changes are cell line-dependent as well as dependent on the surface proteins that interact with EBOV-GP in cis and trans. We have generated data showing that natural killer (NK) cell receptors (NCRs: NKp44 and NKp46), selectins (CD62E/P/L) and inhibitory Siglecs function as receptors for Ebola-GP and human papilloma virus (HPV-L1). We used HEK293 cells transfected with Ebola-GP and recombinant fusion proteins containing the extracellular domain of each of these receptors linked to the Fc of human IgG1, which showed significant differences in their virus-binding behavior compared to HEK293 cells transfected with empty vector. Further, to demonstrate that EBOV-GP is a ligand for NKp44 and other NK-receptors, and to investigate their role in immune escape, we also used human HEK-293, HeLa- and hamster CHO-GP-transfectants. Our data show that the NK receptors NKp44 and NKp46 play a key role in recognizing EBOV (Ebolavirus) and strongly suggest that other inhibitory (Siglec-7, Siglec-5) and non-inhibitory homing receptors (P-Selectin, L-Selectin, E-Selectin, and DC-SIGNR/DC-SIGN) take part in the interaction with virus particles. In addition, we show that NKp44, and NKp46, Siglec-7, and -5, and P-, L-, E-selectins as well as of and DC-SIGNR/DC-SIGN bind to the artificial viral envelope of a lentiviral vector that contains EBOV-GP. Altogether we prove that NCRs and a range of other inhibitory and activating receptors can interact with viral envelope/capsid proteins and that such interaction could play an important role in the elimination of virus infected cells. Our findings could be used to develop new strategies for prevention and treatment of infections by these viruses.Author summaryThe innate immune system is able to recognize specifically certain virus components. Here we show that activating NK-cell receptors (NKp44, and NKp46) are involved in such interaction by using HEK293 and CHOK1 cells transfected with the Ebola virus glycoprotein (EBOV-GP) and by binding studies with purified EBOV-GP. In detail, we have found moderate to strong affinity of Siglecs (Siglec-7, and -5), selectins (P-, L-, E-Selectin) and DC-SIGNR/DC-SIGN to purified EBOV-GP, and to cells transfected with EBOV-GP as well as to the envelope of a lentiviral vector carrying the EBOV-GP. Our findings show that NKp44, and NKp46, Siglec-7, and -5, as well as P-and L-selectins have a strong affinity to EBOV-G.

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“…PCNA intracellular functional range is associated with DNA replication, DNA repair, cell cycle control, apoptosis, chromatin metabolism, and gene expression ( 17 – 19 ). PCNA expression is upregulated in cancer cells relative to healthy normal cells and can be used as a marker of cell proliferation and cancer virulence in many types of cancers ( 9 , 20 – 27 ). Therefore, PCNA is considered as a potential therapeutic target in anticancer therapy ( 28 , 29 ).…”

Section: Introductionmentioning

confidence: 99%

NKp44-Derived Peptide Binds Proliferating Cell Nuclear Antigen and Mediates Tumor Cell Death

et al. 2018

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Proliferating cell nuclear antigen (PCNA) is considered as a hub protein and is a key regulator of DNA replication, repair, cell cycle control, and apoptosis. PCNA is overexpressed in many cancer types, and PCNA overexpression is correlated with cancer virulence. Membrane-associated PCNA is a ligand for the NKp44 (NCR2) innate immune receptor. The purpose of this study was to characterize the PCNA-binding site within NKp44. We have identified NKp44-derived linear peptide (pep8), which can specifically interact with PCNA and partly block the NKp44–PCNA interaction. We then tested whether NKp44-derived pep8 (NKp44-pep8) fused to cell-penetrating peptides (CPPs) can be employed for targeting the intracellular PCNA for the purpose of anticancer therapy. Treatment of tumor cells with NKp44-pep8, fused to R11-NLS cell-penetrating peptide (R11-NLS-pep8), reduced cell viability and promoted cell death, in various murine and human cancer cell lines. Administration of R11-NLS-pep8 to tumor-bearing mice suppressed tumor growth in the 4T1 breast cancer and the B16 melanoma in vivo models. We therefore identified the NKp44 binding site to PCNA and further developed an NKp44-peptide-based agent that can inhibit tumor growth through interfering with the function of intracellular PCNA in the tumor cell.

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NKp44 and NKp30 splice variant profiles in decidua and tumor tissues: a comparative viewpoint

Cited by 14 publications

References 45 publications

Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

Regulation of the Functions of Natural Cytotoxicity Receptors by Interactions with Diverse Ligands and Alterations in Splice Variant Expression

Activating NK- receptors, homing selectins and inhibitory Siglecs recognize EBOLA-GP and HPV-L1NK

NKp44-Derived Peptide Binds Proliferating Cell Nuclear Antigen and Mediates Tumor Cell Death

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