ArticleJournal of immunology (Baltimore, Md. : 1950)2009
PI3K links NKG2D signaling to a CrkL pathway involved in natural killer cell adhesion, polarity, and granule secretion.
Article in Journal of immunology (Baltimore, Md. : 1950), 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 55 citations in OpenAlex.
- G-CSF downregulates natural killer cell-mediated cytotoxicity in donors for hematopoietic SCT.Bone marrow transplantation · 2012Trial
- CAR-CIK vs. CAR-T: benchmarking novel cytokine-induced killer cells as solid tumor immunotherapy in ErbB2+ rhabdomyosarcoma.Frontiers in immunology · 2025Article
- Activation of cytotoxic lymphocytes through CD6 enhances killing of cancer cells.Cancer immunology, immunotherapy : CII · 2024Article
- USP53 Exerts Tumor-Promoting Effects in Triple-Negative Breast Cancer by Deubiquitinating CRKL.Cancers · 2023Article
- Activation of Cytotoxic Lymphocytes Through CD6 Enhances Killing of Cancer Cells.Research square · 2023Article
- Killer instincts: natural killer cells as multifactorial cancer immunotherapy.Frontiers in immunology · 2023Review
- Spatially resolved in silico modeling of NKG2D signaling kinetics suggests a key role of NKG2D and Vav1 Co-clustering in generating natural killer cell activation.PLoS computational biology · 2022Article
- Impact on NK cell functions of acute versus chronic exposure to extracellular vesicle-associated MICA: Dual role in cancer immunosurveillance.Journal of extracellular vesicles · 2022Article
- Current state of NK cell-mediated immunotherapy in chronic lymphocytic leukemia.Frontiers in oncology · 2022Review
- Modeling development of genitourinary birth defects to understand disruption due to changes in gene dosage.American journal of clinical and experimental urology · 2022Review
- Article
- 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
- The septin cytoskeleton regulates natural killer cell lytic granule release.The Journal of cell biology · 2020Article
- Research Progress on NK Cell Receptors and Their Signaling Pathways.Mediators of inflammation · 2020Review
- Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function.The Journal of allergy and clinical immunology · 2020Article
- NKG2D-DAP10 signaling recruits EVL to the cytotoxic synapse to generate F-actin and promote NK cell cytotoxicity.Journal of cell science · 2019Article
- Mutations in PI3K110δ cause impaired natural killer cell function partially rescued by rapamycin treatment.The Journal of allergy and clinical immunology · 2018Article
- Review
- Crk Adaptor Proteins Regulate NK Cell Expansion and Differentiation during Mouse Cytomegalovirus Infection.Journal of immunology (Baltimore, Md. : 1950) · 2018Article
- Phosphoinositide-3-Kinase Signaling in Human Natural Killer Cells: New Insights from Primary Immunodeficiency.Frontiers in immunology · 2018Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The NK cell-activating receptor NKG2D plays a critical role in the destruction of malignant cells, but many of the cell-signaling mechanisms governing NKG2D-mediated cellular cytotoxicity are unknown. We have identified an NKG2D-mediated signaling pathway that governs both conjugate formation and cytotoxic granule polarization. We demonstrate that an interaction between the regulatory subunit of PI3K, p85, and the adaptor protein CrkL is required for efficient NKG2D-mediated cellular cytotoxicity. We show decreased NK cell-target cell conjugate formation in NK cells treated with PI3K inhibitors or depleted of CrkL. Independent of adhesion, we find that microtubule organization center polarization toward target cells expressing the NKG2D ligand MICA or toward anti-NKG2D-coated beads is impaired in the absence of CrkL. Ab-stimulated granule release is also impaired in NK cells depleted of CrkL. Furthermore, our data indicate that the small Ras family GTPase Rap1 is activated downstream of NKG2D engagement in a PI3K- and CrkL-dependent manner and is required for conjugate formation, MTOC (microtubule organizing center) polarization, and NKG2D-dependent cellular cytotoxicity. Taken together, our data identify an NKG2D-activated signaling pathway that collectively orchestrates NK cell adhesion, cell polarization, and granule release.
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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.