ArticleThe Journal of cell biology2011
Release of serine/threonine-phosphorylated adaptors from signaling microclusters down-regulates T cell activation.
Article in The Journal of cell biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
What it found
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Who cites it
35 citing papers in PubMed, 71 citations in OpenAlex.
- HPK1 inhibitor NDI-101150 as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: Phase 1/2 trial results.Cell reports. Medicine · 2026Trial
- LAT condensation gates PLCγ1 activation via bimodal LAT phosphorylation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- From inhibition to degradation: advances in highly selective targeting strategies for HPK1.Molecular diversity · 2026Review
- Highly selective HPK1 inhibitor NDI-101150 mediates immune cell activation and robust antitumor responses, distinct from immune checkpoint blockade.Journal for immunotherapy of cancer · 2025Article
- HPK1 kinase inhibitor: a sufficient approach to target HPK1 to modulate T cell activation in cancer immunotherapy compared with degraders.Frontiers in immunology · 2025Article
- Discovery of BAY-405: An Azaindole-Based MAP4K1 Inhibitor for the Enhancement of T-Cell Immunity against Cancer.Journal of medicinal chemistry · 2024Article
- HPK1 citron homology domain regulates phosphorylation of SLP76 and modulates kinase domain interaction dynamics.Nature communications · 2024Article
- An updated review of small-molecule HPK1 kinase inhibitors (2016-present).Future medicinal chemistry · 2024Review
- Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets.Journal for immunotherapy of cancer · 2023Review
- Systems-level conservation of the proximal TCR signaling network of mice and humans.The Journal of experimental medicine · 2022Article
- Article
- Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening.Frontiers in pharmacology · 2022Article
- Advancing targeted protein degradation for cancer therapy.Nature reviews. Cancer · 2021Review
- Itk Promotes the Integration of TCR and CD28 Costimulation through Its Direct Substrates SLP-76 and Gads.Journal of immunology (Baltimore, Md. : 1950) · 2021Article
- Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds.ACS medicinal chemistry letters · 2021Article
- Using yeast surface display to engineer a soluble and crystallizable construct of hematopoietic progenitor kinase 1 (HPK1).Acta crystallographica. Section F, Structural biology communications · 2021Article
- Review
- Chrysophanol Mitigates T Cell Activation by Regulating the Expression of CD40 Ligand in Activated T Cells.International journal of molecular sciences · 2020Article
- Coordinating Cytoskeleton and Molecular Traffic in T Cell Migration, Activation, and Effector Functions.Frontiers in cell and developmental biology · 2020Review
- Microclusters as T Cell Signaling Hubs: Structure, Kinetics, and Regulation.Frontiers in cell and developmental biology · 2020Review
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Antigen recognition within immunological synapses triggers and sustains T cell activation by nucleating protein microclusters that gather T cell receptors (TCRs), kinases, and adaptors. Dissipation of these microclusters results in signal termination, but how this process is regulated is unclear. In this paper, we reveal that release of the adaptors SLP76 and GADS from signaling microclusters is induced by the serine/threonine protein kinase HPK1 and that phosphorylation of GADS plays a major role in this process. We found that HPK1 was recruited into microclusters and triggered their dissipation by inducing the phosphorylation of a threonine-containing motif of GADS, together with the previously described serine phosphorylation of SLP76. These events induced the cooperative binding of 14-3-3 proteins to SLP76-GADS complexes, leading to their uncoupling from the transmembrane adaptor LAT and consequently reducing microcluster persistence and activation-induced gene transcription. These results demonstrate that serine/threonine phosphorylation of multiple TCR-proximal effectors controls the stability of signaling microclusters, thereby determining the intensity of T cell responses.
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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.