Molecular Mechanisms for CAMP-Mediated Immunoregulation in T Cells - Role of Anchored Protein Kinase A Signaling Units

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2016 Jul 5

PMID 27375620

Citations 90

Authors

Vanessa L Wehbi

Kjetil Tasken

Affiliations

Soon will be listed here.

Abstract

The cyclic AMP/protein kinase A (cAMP/PKA) pathway is one of the most common and versatile signal pathways in eukaryotic cells. A-kinase anchoring proteins (AKAPs) target PKA to specific substrates and distinct subcellular compartments providing spatial and temporal specificity for mediation of biological effects channeled through the cAMP/PKA pathway. In the immune system, cAMP is a potent negative regulator of T cell receptor-mediated activation of effector T cells (Teff) acting through a proximal PKA/Csk/Lck pathway anchored via a scaffold consisting of the AKAP Ezrin holding PKA, the linker protein EBP50, and the anchoring protein phosphoprotein associated with glycosphingolipid-enriched microdomains holding Csk. As PKA activates Csk and Csk inhibits Lck, this pathway in response to cAMP shuts down proximal T cell activation. This immunomodulating pathway in Teff mediates clinically important responses to regulatory T cell (Treg) suppression and inflammatory mediators, such as prostaglandins (PGs), adrenergic stimuli, adenosine, and a number of other ligands. A major inducer of T cell cAMP levels is PG E2 (PGE2) acting through EP2 and EP4 prostanoid receptors. PGE2 plays a crucial role in the normal physiological control of immune homeostasis as well as in inflammation and cancer immune evasion. Peripherally induced Tregs express cyclooxygenase-2, secrete PGE2, and elicit the immunosuppressive cAMP pathway in Teff as one tumor immune evasion mechanism. Moreover, a cAMP increase can also be induced by indirect mechanisms, such as intercellular transfer between T cells. Indeed, Treg, known to have elevated levels of intracellular cAMP, may mediate their suppressive function by transferring cAMP to Teff through gap junctions, which we speculate could also be regulated by PKA/AKAP complexes. In this review, we present an updated overview on the influence of cAMP-mediated immunoregulatory mechanisms acting through localized cAMP signaling and the therapeutical increasing prospects of AKAPs disruptors in T-cell immune function.

Citing Articles

GPR132 regulates the function of NK cells through the Gαs/CSK/ZAP70/NF-κB signaling pathway as a potential immune checkpoint.

Hui X, Xue M, Ren Y, Chen Y, Chen X, Farooq M Sci Adv. 2025; 11(10):eadr9395.

PMID: 40043109 PMC: 11881902. DOI: 10.1126/sciadv.adr9395.

Exploring the interaction between the gut microbiota and cyclic adenosine monophosphate-protein kinase A signaling pathway: a potential therapeutic approach for neurodegenerative diseases.

Deng F, Yang D, Qing L, Chen Y, Zou J, Jia M Neural Regen Res. 2024; 20(11):3095-3112.

PMID: 39589173 PMC: 11881707. DOI: 10.4103/NRR.NRR-D-24-00607.

and pharmacological evaluation of GPR65 as a cancer immunotherapy target regulating T-cell functions.

Li S, Melchiore F, Kantari-Mimoun C, Mouton A, Knockaert S, Philippon W Front Immunol. 2024; 15:1483258.

PMID: 39483470 PMC: 11525786. DOI: 10.3389/fimmu.2024.1483258.

Neuropeptide signalling orchestrates T cell differentiation.

Hou Y, Sun L, LaFleur M, Huang L, Lambden C, Thakore P Nature. 2024; 635(8038):444-452.

PMID: 39415015 DOI: 10.1038/s41586-024-08049-w.

Germline mutations in a G protein identify signaling cross-talk in T cells.

Ham H, Jing H, Lamborn I, Kober M, Koval A, Berchiche Y Science. 2024; 385(6715):eadd8947.

PMID: 39298586 PMC: 11811912. DOI: 10.1126/science.add8947.

References

Egerton M, Burgess W, Chen D, Druker B, BRETSCHER A, Samelson L . Identification of ezrin as an 81-kDa tyrosine-phosphorylated protein in T cells. J Immunol. 1992; 149(6):1847-52. View

Kawabuchi M, Satomi Y, Takao T, Shimonishi Y, Nada S, Nagai K . Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature. 2000; 404(6781):999-1003. DOI: 10.1038/35010121. View

Houslay M, Milligan G . Tailoring cAMP-signalling responses through isoform multiplicity. Trends Biochem Sci. 1997; 22(6):217-24. DOI: 10.1016/s0968-0004(97)01050-5. View

Henney C, Lichtenstein L . The role of cyclic AMP in the cytolytic activity of lymphocytes. J Immunol. 1971; 107(2):610-2. View

Gupta R, DuBois R . Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 2002; 1(1):11-21. DOI: 10.1038/35094017. View

Coghlan V, Langeberg L, Fernandez A, Lamb N, Scott J . Cloning and characterization of AKAP 95, a nuclear protein that associates with the regulatory subunit of type II cAMP-dependent protein kinase. J Biol Chem. 1994; 269(10):7658-65. View

Perry S, Baillie G, Kohout T, McPhee I, Magiera M, Ang K . Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science. 2002; 298(5594):834-6. DOI: 10.1126/science.1074683. View

Wen A, Sakamoto K, Miller L . The role of the transcription factor CREB in immune function. J Immunol. 2010; 185(11):6413-9. PMC: 5519339. DOI: 10.4049/jimmunol.1001829. View

Rincon M, Tugores A, Lopez-Rivas A, Silva A, Alonso M, de Landazuri M . Prostaglandin E2 and the increase of intracellular cAMP inhibit the expression of interleukin 2 receptors in human T cells. Eur J Immunol. 1988; 18(11):1791-6. DOI: 10.1002/eji.1830181121. View

10.

Williams R . Cutting edge: A-kinase anchor proteins are involved in maintaining resting T cells in an inactive state. J Immunol. 2002; 168(11):5392-6. DOI: 10.4049/jimmunol.168.11.5392. View

11.

Pakkanen R, Hedman K, Turunen O, Wahlstrom T, Vaheri A . Microvillus-specific Mr 75,000 plasma membrane protein of human choriocarcinoma cells. J Histochem Cytochem. 1987; 35(8):809-16. DOI: 10.1177/35.8.3298422. View

12.

BRETSCHER A . Regulation of cortical structure by the ezrin-radixin-moesin protein family. Curr Opin Cell Biol. 1999; 11(1):109-16. DOI: 10.1016/s0955-0674(99)80013-1. View

13.

Yaqub S, Henjum K, Mahic M, Jahnsen F, Aandahl E, Bjornbeth B . Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner. Cancer Immunol Immunother. 2007; 57(6):813-21. PMC: 11030670. DOI: 10.1007/s00262-007-0417-x. View

14.

Aukrust P, Aandahl E, Skalhegg B, Nordoy I, Hansson V, Tasken K . Increased activation of protein kinase A type I contributes to the T cell deficiency in common variable immunodeficiency. J Immunol. 1999; 162(2):1178-85. View

15.

Bretscher A, Edwards K, Fehon R . ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol. 2002; 3(8):586-99. DOI: 10.1038/nrm882. View

16.

Tsujii M, DuBois R . Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995; 83(3):493-501. DOI: 10.1016/0092-8674(95)90127-2. View

17.

Bjorgo E, Moltu K, Tasken K . Phosphodiesterases as targets for modulating T-cell responses. Handb Exp Pharmacol. 2011; (204):345-63. DOI: 10.1007/978-3-642-17969-3_15. View

18.

Wong W, Scott J . AKAP signalling complexes: focal points in space and time. Nat Rev Mol Cell Biol. 2004; 5(12):959-70. DOI: 10.1038/nrm1527. View

19.

Sheng H, Shao J, Morrow J, Beauchamp R, DuBois R . Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells. Cancer Res. 1998; 58(2):362-6. View

20.

Shcherbina A, BRETSCHER A, Kenney D, Remold-ODonnell E . Moesin, the major ERM protein of lymphocytes and platelets, differs from ezrin in its insensitivity to calpain. FEBS Lett. 1999; 443(1):31-6. DOI: 10.1016/s0014-5793(98)01674-3. View