ArticleScience signaling2012
Complementary phosphorylation sites in the adaptor protein SLP-76 promote synergistic activation of natural killer cells.
Article in Science signaling, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 68 citations in OpenAlex.
- Resting-state spatial statistics of NK cell receptors may improve early signal discrimination.Biophysical journal · 2026Article
- Natural Killer Cell-Mediated Antitumor Immunity: Molecular Mechanisms and Clinical Applications.MedComm · 2025Review
- Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization.Signal transduction and targeted therapy · 2024Review
- Revisiting T-cell adhesion molecules as potential targets for cancer immunotherapy: CD226 and CD2.Experimental & molecular medicine · 2024Review
- HPK1 Dysregulation-Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Using In silico models to predict lymphocyte activation and development in a data rich era.Immunoinformatics (Amsterdam, Netherlands) · 2024Article
- Dysregulation of DNAM-1-Mediated NK Cell Anti-Cancer Responses in the Tumor Microenvironment.Cancers · 2023Review
- Human natural killer cells: Form, function, and development.The Journal of allergy and clinical immunology · 2023Review
- Taking Lessons from CAR-T Cells and Going Beyond: Tailoring Design and Signaling for CAR-NK Cells in Cancer Therapy.Frontiers in immunology · 2022Review
- Identification of prognostic biomarkers associated with tumor microenvironment in ceRNA network for esophageal squamous cell carcinoma: a bioinformatics study based on TCGA database.Discover oncology · 2021Article
- Review
- Poliovirus receptor (PVR)-like protein cosignaling network: new opportunities for cancer immunotherapy.Journal of experimental & clinical cancer research : CR · 2021Review
- Tumor-derived NKG2D ligand sMIC reprograms NK cells to an inflammatory phenotype through CBM signalosome activation.Communications biology · 2021Article
- TIGIT/CD226 Axis Regulates Anti-Tumor Immunity.Pharmaceuticals (Basel, Switzerland) · 2021Review
- The Role of the Cytoskeleton in Regulating the Natural Killer Cell Immune Response in Health and Disease: From Signaling Dynamics to Function.Frontiers in cell and developmental biology · 2021Review
- An optimal control approach for enhancing natural killer cells' secretion of cytolytic molecules.APL bioengineering · 2020Article
- CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma.Journal of hematology & oncology · 2020Review
- Enhancing network activation in natural killer cells: predictions from in silico modeling.Integrative biology : quantitative biosciences from nano to macro · 2020Article
- PD-1 Expression on NK Cells in Malaria-Exposed Individuals Is Associated with Diminished Natural Cytotoxicity and Enhanced Antibody-Dependent Cellular Cytotoxicity.Infection and immunity · 2020Article
- Research Progress on NK Cell Receptors and Their Signaling Pathways.Mediators of inflammation · 2020Review
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
Abstract
The cytotoxic effects of natural killer (NK) cells and their ability to secrete cytokines require synergistic signals from specific pairs of co-activation receptors, such as CD314 (also known as NKG2D) and CD244 (2B4), which bind to distinct ligands present on target cells. These signals are required to overcome inhibition mediated by the E3 ubiquitin ligase c-Cbl of the guanine nucleotide exchange factor Vav1, which promotes activation of NK cells. Here, we showed that the adaptor protein SLP-76 (Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons) was required for this synergy and that distinct tyrosine residues in SLP-76 were phosphorylated by each member of a pair of synergistic receptors. Selective phosphorylation of tyrosine 113 or tyrosine 128 in SLP-76 enabled binding of SLP-76 to Vav1. Selective phosphorylation of SLP-76 at these residues was restricted to receptors that stimulated ligand-dependent target cell killing; antibody-dependent stimulation of the Fc receptor CD16 promoted phosphorylation at both sites. Knockdown and reconstitution experiments with SLP-76 mutant proteins showed the distinct role of each tyrosine in the synergistic mobilization of Ca2+, revealing an unexpected degree of selectivity in the phosphorylation of SLP-76 by NK cell co-activation receptors. Together, these data suggest that combined phosphorylation of separate tyrosine residues in SLP-76 forms the basis of synergistic NK cell activation.
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Registered trials
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.