ArticleThe Journal of experimental medicine2007
A novel pathway down-modulating T cell activation involves HPK-1-dependent recruitment of 14-3-3 proteins on SLP-76.
Article in The Journal of experimental medicine, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 106 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
- From inhibition to degradation: advances in highly selective targeting strategies for HPK1.Molecular diversity · 2026Review
- C-terminus CD28 phosphorylation (Y218) modulates IL-2 secretion and antitumor effect of CAR-T cells.bioRxiv : the preprint server for biology · 2026Article
- 14-3-3 Proteins Negatively Regulate Microglial Activation via Inhibition of the NF-κB Pathway.Journal of neurochemistry · 2025Article
- 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 Dysregulation-Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- HPK1 citron homology domain regulates phosphorylation of SLP76 and modulates kinase domain interaction dynamics.Nature communications · 2024Article
- 14-3-3ε: a protein with complex physiology function but promising therapeutic potential in cancer.Cell communication and signaling : CCS · 2024Review
- The guanine nucleotide exchange factor Rin-like controls Tfh cell differentiation via CD28 signaling.The Journal of experimental medicine · 2023Article
- Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets.Journal for immunotherapy of cancer · 2023Review
- Disruption of CISH promotes the antitumor activity of human T cells and decreases PD-1 expression levels.Molecular therapy oncolytics · 2023Article
- Theoretical Studies on Selectivity of HPK1/JAK1 Inhibitors by Molecular Dynamics Simulations and Free Energy Calculations.International journal of molecular sciences · 2023Article
- Small molecule inhibitors for cancer immunotherapy and associated biomarkers - the current status.Frontiers in immunology · 2023Review
- The expanding role for small molecules in immuno-oncology.Nature reviews. Drug discovery · 2022Review
- Systems-level conservation of the proximal TCR signaling network of mice and humans.The Journal of experimental medicine · 2022Article
- Discovery of Novel HPK1 Inhibitors Through Structure-Based Virtual Screening.Frontiers in pharmacology · 2022Article
- Identification of molecular glues of the SLP76/14-3-3 protein-protein interaction.RSC medicinal chemistry · 2021Article
- Itk Promotes the Integration of TCR and CD28 Costimulation through Its Direct Substrates SLP-76 and Gads.Journal of immunology (Baltimore, Md. : 1950) · 2021Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The SH2 domain-containing leukocyte protein of 76 kD (SLP-76) is a pivotal element of the signaling machinery controlling T cell receptor (TCR)-mediated activation. Here, we identify 14-3-3epsilon and zeta proteins as SLP-76 binding partners. This interaction was induced by TCR ligation and required phosphorylation of SLP-76 at serine 376. Ribonucleic acid interference and in vitro phosphorylation experiments showed that serine 376 is the target of the hematopoietic progenitor kinase 1 (HPK-1). Interestingly, either S376A mutation or HPK-1 knockdown resulted in increased TCR-induced tyrosine phosphorylation of SLP-76 and phospholipase C-gamma1. Moreover, an SLP-76-S376A mutant induced higher interleukin 2 gene transcription than wild-type SLP-76. These data reveal a novel negative feedback loop involving HPK-1-dependent serine phosphorylation of SLP-76 and 14-3-3 protein recruitment, which tunes T 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 Socratic graph.