ArticleScience signaling2016
Dephosphorylation of the adaptor LAT and phospholipase C-γ by SHP-1 inhibits natural killer cell cytotoxicity.
Article in Science signaling, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 71 citations in OpenAlex.
- Recent Advances in Research on SHP Family Phosphatases: Signal Regulation Mechanisms and Disease Associations.Cell biochemistry and function · 2026Review
- Genetic manipulation of OGT enhances NK cell-mediated cytotoxicity in tumor immunity.Journal of advanced research · 2026Article
- Basal phosphorylation of SHIP1 by Lyn suppresses proinflammatory signaling in the absence of a phagocytic synapse.Journal of immunology (Baltimore, Md. : 1950) · 2026Article
- Phosphoproteomic analysis of successive Jurkat CD19-CAR generations reveals TCRζ-driven signalling.Cellular signalling · 2026Article
- From pathogenesis to therapeutic targeting: new insight into TAM receptors in rheumatoid arthritis.Cell & bioscience · 2025Review
- Ubiquitin modification in the regulation of tumor immunotherapy resistance mechanisms and potential therapeutic targets.Experimental hematology & oncology · 2024Review
- NKG2A genetic deletion promotes human primary NK cell anti-tumor responses better than an anti-NKG2A monoclonal antibody.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Lck Function and Modulation: Immune Cytotoxic Response and Tumor Treatment More Than a Simple Event.Cancers · 2024Review
- Dysfunctional natural killer cells can be reprogrammed to regain anti-tumor activity.The EMBO journal · 2024Article
- Natural Killer Cell Mechanosensing in Solid Tumors.Bioengineering (Basel, Switzerland) · 2024Review
- THEMIS is a substrate and allosteric activator of SHP1, playing dual roles during T cell development.Nature structural & molecular biology · 2024Article
- Human PLCG2 haploinsufficiency results in a novel natural killer cell immunodeficiency.The Journal of allergy and clinical immunology · 2024Article
- ADSC secretome constrains NK cell activity by attenuating IL-2-mediated JAK-STAT and AKT signaling pathway via upregulation of CIS and DUSP4.Stem cell research & therapy · 2023Article
- Human natural killer cells: Form, function, and development.The Journal of allergy and clinical immunology · 2023Review
- Natural Killer Cell-Based Immunotherapy against Glioblastoma.International journal of molecular sciences · 2023Review
- Actin cytoskeleton remodeling at the cancer cell side of the immunological synapse: good, bad, or both?Frontiers in immunology · 2023Review
- Actin Retrograde Flow Regulated by the Wiskott-Aldrich Syndrome Protein Drives the Natural Killer Cell Response.Cancers · 2022Article
- NK cell dysfunction is linked with disease severity in SARS-CoV-2 patients.Cell biochemistry and function · 2022Review
- Acoustofluidic Stimulation of Functional Immune Cells in a Microreactor.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Negative times negative equals positive, THEMIS sets the rule on thymic selection and peripheral T cell responses.Biomedical journal · 2022Review
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Natural killer (NK) cells discriminate between healthy cells and virally infected or transformed self-cells by tuning activating and inhibitory signals received through cell surface receptors. Inhibitory receptors inhibit NK cell function by recruiting and activating the tyrosine phosphatase Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-1 (SHP-1) to the plasma membrane. However, to date, the guanine nucleotide exchange factor VAV1 is the only direct SHP-1 substrate identified in NK cells. We reveal that the adaptor protein linker for activation of T cells (LAT) as well as phospholipase C-γ1 (PLC-γ1) and PLC-γ2 are SHP-1 substrates. Dephosphorylation of Tyr(132) in LAT by SHP-1 in NK cells abrogated the recruitment of PLC-γ1 and PLC-γ2 to the immunological synapse between the NK cell and a cancer cell target, which reduced NK cell degranulation and target cell killing. Furthermore, the ubiquitylation of LAT by the E3 ubiquitin ligases c-Cbl and Cbl-b, which was induced by LAT phosphorylation, led to the degradation of LAT in response to the engagement of inhibitory receptors on NK cells, which abrogated NK cell cytotoxicity. Knockdown of the Cbl proteins blocked LAT ubiquitylation, which promoted NK cell function. Expression of a ubiquitylation-resistant mutant LAT blocked inhibitory receptor signaling, enabling cells to become activated. Together, these data identify previously uncharacterized SHP-1 substrates and inhibitory mechanisms that determine the response of NK cells.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.