Activation of the Cooh-Terminal Src Kinase (Csk) by Camp-Dependent Protein Kinase Inhibits Signaling through the T Cell Receptor
Open accessAbstract
In T cells, cAMP-dependent protein kinase (PKA) type I colocalizes with the T cell receptor–CD3 complex (TCR/CD3) and inhibits T cell function via a previously unknown proximal target. Here we examine the mechanism for this PKA-mediated immunomodulation. cAMP treatment of Jurkat and normal T cells reduces Lck-mediated tyrosine phosphorylation of the TCR/CD3 ζ chain after T cell activation, and decreases Lck activity. Phosphorylation of residue Y505 in Lck by COOH-terminal Src kinase (Csk), which negatively regulates Lck, is essential for the inhibitory effect of cAMP on ζ chain phosphorylation. PKA phosphorylates Csk at S364 in vitro and in vivo leading to a two- to fourfold increase in Csk activity that is necessary for cAMP-mediated inhibition of TCR-induced interleukin 2 secretion. Both PKA type I and Csk are targeted to lipid rafts where proximal T cell activation occurs, and phosphorylation of raft-associated Lck by Csk is increased in cells treated with forskolin. We propose a mechanism whereby PKA through activation of Csk intersects signaling by Src kinases and inhibits T cell activation.
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Many factors in the tumor microenvironment, including cAMP, glucose competition, and oncogenic stress, can induce senescence of T cells, macrophages, natural killer cells, and dendritic cells.
“The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells.”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [57]
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From Immunosenescence: a key player in cancer development (2020) · cites this paper as [57]
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- Authors
- Vang, T., Torgersen, K. M., Sundvold, V., Saxena, M., Levy, F. O., Skålhegg, B. S., Hansson, V., Mustelin, T., & Taskén, K.
- Affiliations
- University of Oslo (NO)
- La Jolla Institute for Immunology (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2001-02-19
- Volume
- 193
- Issue
- 4
- Pages
- 497-508
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2195911
- OpenAlex
- W2163905724
- Cited by
- 330
- References
- 42
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 9 · 2023: 13 · 2022: 17 · 2021: 13 · 2020: 8 · 2019: 11 · 2018: 10 · 2017: 7 · 2016: 15 · 2015: 10 · 2014: 6 · 2013: 19 · 2012: 10
- FWCI
- 7.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1r01ai041481-01)
- National Institute of Allergy and Infectious Diseases (R01AI035603, AI41481, AI48032, AI40552, AI 35603, R01AI048032)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- protein kinase A, T cell receptor signaling, T cell activation, interleukin-2 secretion, lipid rafts, immunomodulation, cAMP signaling
- MeSH terms
- CSK Tyrosine-Protein Kinase, Cells, Cultured, Enzyme Activation, Humans, Lymphocyte Activation, Phosphorylation, Protein-Tyrosine Kinases, Receptors, Antigen, T-Cell, T-Lymphocytes, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Models, Immunological, src-Family Kinases, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), Membrane Microdomains
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