Isoform-specific regulation of immune cell reactivity by the catalytic subunit of protein kinase A (PKA)

Funderud, Ane; Aas-Hanssen, Kristin; Aksaas, Anne Kristin; Hafte, Tilahun Tolesa; Corthay, Alexandre; Munthe, Ludvig A.; Ørstavik, Sigurd; Skålhegg, Bjørn Steen

doi:10.1016/j.cellsig.2008.10.013

Cited by 22 publications

(17 citation statements)

References 40 publications

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“…Furthermore, Th CSE upregulated TFs EGR1 and JUND and downregulated protein kinase A genes ( PRKACB) , which are important regulators of T cell activation and differentiation (35, 36). …”

Section: Resultsmentioning

confidence: 99%

Th17 Polarization under Hypoxia Results in Increased IL-10 Production in a Pathogen-Independent Manner

et al. 2017

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The IL-17-producing CD4+ T helper cell (Th17) differentiation is affected by stimulation of the aryl hydrocarbon receptor (AhR) pathway and by hypoxia-inducible factor 1 alpha (HIF-1α). In some cases, Th17 become non-pathogenic and produce IL-10. However, the initiating events triggering this phenotype are yet to be fully understood. Here, we show that such cells may be differentiated at low oxygen and regardless of AhR ligand treatment such as cigarette smoke extract. Hypoxia led to marked alterations of the transcriptome of IL-10-producing Th17 cells affecting genes involved in metabolic, anti-apoptotic, cell cycle, and T cell functional pathways. Moreover, we show that oxygen regulates the expression of CD52, which is a cell surface protein that has been shown to suppress the activation of other T cells upon release. Taken together, these findings suggest a novel ability for Th17 cells to regulate immune responses in vivo in an oxygen-dependent fashion.

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“…Furthermore, Th CSE upregulated TFs EGR1 and JUND and downregulated protein kinase A genes ( PRKACB) , which are important regulators of T cell activation and differentiation (35, 36). …”

Section: Resultsmentioning

confidence: 99%

Th17 Polarization under Hypoxia Results in Increased IL-10 Production in a Pathogen-Independent Manner

et al. 2017

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“…Furthermore, neither siRNAs affect the expression of the PKA catalytic subunits expressed in T lymphocytes: PKAC␣1, PKAC␤ 1 , and PKAC␤ 2 ( Fig. 2A) (15). Consequently, PKAI siRNAs inhibited the expression of PKA-RI but not PKA-RII protein (Fig.…”

Section: Pka Modulates the Activity Of K V 13 Channels In Human T Lymentioning

confidence: 92%

Modulation of K_V1.3 channels by protein kinase A I in T lymphocytes is mediated by the disc large 1-tyrosine kinase Lck complex

Kuras¹,

Kucher²,

Gordon³

et al. 2012

American Journal of Physiology-Cell Physiology

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The cAMP/PKA signaling system constitutes an inhibitory pathway in T cells and, although its biochemistry has been thoroughly investigated, its possible effects on ion channels are still not fully understood. K(V)1.3 channels play an important role in T-cell activation, and their inhibition suppresses T-cell function. It has been reported that PKA modulates K(V)1.3 activity. Two PKA isoforms are expressed in human T cells: PKAI and PKAII. PKAI has been shown to inhibit T-cell activation via suppression of the tyrosine kinase Lck. The aim of this study was to determine the PKA isoform modulating K(V)1.3 and the signaling pathway underneath. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP), a nonselective activator of PKA, inhibited K(V)1.3 currents both in primary human T and in Jurkat cells. This inhibition was prevented by the PKA blocker PKI(6-22). Selective knockdown of PKAI, but not PKAII, with siRNAs abolished the response to 8-BrcAMP. Additional studies were performed to determine the signaling pathway mediating PKAI effect on K(V)1.3. Overexpression of a constitutively active mutant of Lck reduced the response of K(V)1.3 to 8-Br-cAMP. Moreover, knockdown of the scaffolding protein disc large 1 (Dlg1), which binds K(V)1.3 to Lck, abolished PKA modulation of K(V)1.3 channels. Immunohistochemistry studies showed that PKAI, but not PKAII, colocalizes with K(V)1.3 and Dlg1 indicating a close proximity between these proteins. These results indicate that PKAI selectively regulates K(V)1.3 channels in human T lymphocytes. This effect is mediated by Lck and Dlg1. We thus propose that the K(V)1.3/Dlg1/Lck complex is part of the membrane pathway that cAMP utilizes to regulate T-cell function.

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“…With the exception of PKA and CSK, the expression of these kinases is predominantly restricted to immune cells, suggesting selective roles in immune modulation. Accordingly, genetically engineered mouse models enabling the abrogation of PKA, CSK, MAP4K1, or DGKξ functions exhibit hallmarks of excessive immune activation and/or TCR hypersensitivity (128,(130)(131)(132) -/-mice, the role of these kinases in tumor immune surveillance has already been established, confirming the viability of these approaches for restoring antitumor immunity (131,133). In contrast, ubiquitous expression and pleiotropic functions of CSK and PKA may limit the viability of these targets in this context.…”

Section: Future Directionsmentioning

confidence: 94%

Targeting cancer with kinase inhibitors

Größ¹,

Rahal²,

Stransky³

et al. 2015

J. Clin. Invest.

383

289

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Isoform-specific regulation of immune cell reactivity by the catalytic subunit of protein kinase A (PKA)

Cited by 22 publications

References 40 publications

Th17 Polarization under Hypoxia Results in Increased IL-10 Production in a Pathogen-Independent Manner

Th17 Polarization under Hypoxia Results in Increased IL-10 Production in a Pathogen-Independent Manner

Modulation of K_V1.3 channels by protein kinase A I in T lymphocytes is mediated by the disc large 1-tyrosine kinase Lck complex

Targeting cancer with kinase inhibitors

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Isoform-specific regulation of immune cell reactivity by the catalytic subunit of protein kinase A (PKA)

Cited by 22 publications

References 40 publications

Th17 Polarization under Hypoxia Results in Increased IL-10 Production in a Pathogen-Independent Manner

Th17 Polarization under Hypoxia Results in Increased IL-10 Production in a Pathogen-Independent Manner

Modulation of KV1.3 channels by protein kinase A I in T lymphocytes is mediated by the disc large 1-tyrosine kinase Lck complex

Targeting cancer with kinase inhibitors

Contact Info

Product

Resources

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Modulation of K_V1.3 channels by protein kinase A I in T lymphocytes is mediated by the disc large 1-tyrosine kinase Lck complex