ArticleProceedings of the National Academy of Sciences of the United States of America1995
p56Lck and p59Fyn regulate CD28 binding to phosphatidylinositol 3-kinase, growth factor receptor-bound protein GRB-2, and T cell-specific protein-tyrosine kinase ITK: implications for T-cell costimulation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1995. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 167 citations in OpenAlex.
- microRNAs as Regulators of the Immune Response and Their Potential Therapeutic Applications in Cancer.Non-coding RNA · 2026Review
- CD28 signaling complexes are correlated with patient outcomes in anti-CD19 41BB-costimulation CAR T cell therapy.Journal for immunotherapy of cancer · 2025Article
- Farnesoid X Receptor Agonist Tropifexor Improves Intestinal Defense Response and Epithelial Barrier Function in Neonatal Piglets Receiving Parenteral Nutrition.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- CD4/CD8-p56Biomolecules · 2025Review
- An engineered viral protein activates STAT5 to prevent T cell suppression.Science immunology · 2025Article
- Advances in CAR optimization strategies based on CD28.Frontiers in immunology · 2025Review
- CD28 co-stimulation: novel insights and applications in cancer immunotherapy.Nature reviews. Immunology · 2024Review
- CD28-CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance.Cell reports. Medicine · 2023Article
- Balancing activation and co-stimulation of CAR tunes signaling dynamics and enhances therapeutic potency.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- CD28 and chemokine receptors: Signalling amplifiers at the immunological synapse.Frontiers in immunology · 2022Review
- Implications of a 'Third Signal' in NK Cells.Cells · 2021Review
- Naturally Occurring Genetic Alterations in Proximal TCR Signaling and Implications for Cancer Immunotherapy.Frontiers in immunology · 2021Review
- How the Discovery of the CD4/CD8-p56Frontiers in cell and developmental biology · 2021Review
- The phosphorylation of CD147 by Fyn plays a critical role for melanoma cells growth and metastasis.Oncogene · 2020Article
- Glycogen Synthase Kinase 3 Inactivation Compensates for the Lack of CD28 in the Priming of CD8Frontiers in immunology · 2017Article
- Membrane Rafts in T Cell Activation: A Spotlight on CD28 Costimulation.Frontiers in immunology · 2017Review
- CD28 family of receptors inter-connect in the regulation of T-cells.Receptors & clinical investigation · 2017Article
- Binding of the cytoplasmic domain of CD28 to the plasma membrane inhibits Lck recruitment and signaling.Science signaling · 2016Article
- CD28 Costimulation: From Mechanism to Therapy.Immunity · 2016Review
- Signaling in Effector Lymphocytes: Insights toward Safer Immunotherapy.Frontiers in immunology · 2016Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
T-cell activation requires cooperative signals generated by the T-cell antigen receptor zeta-chain complex (TCR zeta-CD3) and the costimulatory antigen CD28. CD28 interacts with three intracellular proteins-phosphatidylinositol 3-kinase (PI 3-kinase), T cell-specific protein-tyrosine kinase ITK (formerly TSK or EMT), and the complex between growth factor receptor-bound protein 2 and son of sevenless guanine nucleotide exchange protein (GRB-2-SOS). PI 3-kinase and GRB-2 bind to the CD28 phosphotyrosine-based Tyr-Met-Asn-Met motif by means of intrinsic Src-homology 2 (SH2) domains. The requirement for tyrosine phosphorylation of the Tyr-Met-Asn-Met motif for SH2 domain binding implicates an intervening protein-tyrosine kinase in the recruitment of PI 3-kinase and GRB-2 by CD28. Candidate kinases include p56Lck, p59Fyn, zeta-chain-associated 70-kDa protein (ZAP-70), and ITK. In this study, we demonstrate in coexpression studies that p56Lck and p59Fyn phosphorylate CD28 primarily at Tyr-191 of the Tyr-Met-Asn-Met motif, inducing a 3- to 8-fold increase in p85 (subunit of PI 3-kinase) and GRB-2 SH2 binding to CD28. Phosphatase digestion of CD28 eliminated binding. In contrast to Src kinases, ZAP-70 and ITK failed to induce these events. Further, ITK binding to CD28 was dependent on the presence of p56Lck and is thus likely to act downstream of p56Lck/p59Fyn in a signaling cascade. p56Lck is therefore likely to be a central switch in T-cell activation, with the dual function of regulating CD28-mediated costimulation as well as TCR-CD3-CD4 signaling.
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What OpenQuestion holds
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.