Molecular mechanisms for protein kinase A-mediated modulation of immune function

Torgersen, Knut Martin; Vang, Torkel; Abrahamsen, Hilde; Yaqub, Sheraz; Taskén, Kjetil

doi:10.1016/s0898-6568(01)00214-5

Cited by 175 publications

(152 citation statements)

References 114 publications

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“…PKA is activated by broad cellular processes to target multiple substrates with specificity conferred through the assembly of various combinations of regulatory and catalytic subunits and the subcompartmentalization of the signaling module by kinase-anchoring proteins (46,47). PKA signaling is also regulated by cellular tonicity (36).…”

Section: Discussionmentioning

confidence: 99%

cAMP-dependent Protein Kinase and c-Jun N-terminal Kinase Mediate Stathmin Phosphorylation for the Maintenance of Interphase Microtubules during Osmotic Stress

Yip

Yeap

Bogoyevitch

et al. 2014

Journal of Biological Chemistry

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Background: Complex phosphorylation mechanisms negatively regulate stathmin microtubule-destabilizing activity. Results: Stathmin is co-regulated by JNK and PKA to maintain the integrity of interphase microtubules during hyperosmotic stress. Conclusion: Stress-activated JNK and PKA pathways are integrated in the regulation of the microtubule array during cell stress. Significance: Stress signaling regulation of microtubule destabilizing stathmin is critical in determining cytoskeleton organization in response to cell stress.

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Section: Discussionmentioning

confidence: 99%

cAMP-dependent Protein Kinase and c-Jun N-terminal Kinase Mediate Stathmin Phosphorylation for the Maintenance of Interphase Microtubules during Osmotic Stress

Yip

Yeap

Bogoyevitch

et al. 2014

Journal of Biological Chemistry

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“…The I B binding by each of these proteins has certain impact on NF-B pathway. It has been shown that NF-B activation can be regulated by protein kinase A by both cAMP-dependent and cAMP-independent mechanisms (33). Moreover, it has been established that cAMP signaling is highly compartmentalized (34,35).…”

Section: Discussionmentioning

confidence: 99%

Per-Arnt-Sim domain-dependent association of cAMP-phosphodiesterase 8A1 with IκB proteins

Wang¹

2004

Proc. Natl. Acad. Sci. U.S.A.

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Phosphodiesterase (PDE) 8A1 is a cAMP-specific PDE isozyme characterized by the presence of a Per-Arnt-Sim (PAS) domain. However, the function(s) of the PAS domain has remained unknown. In this study, using a lysate of HEK293 cells overexpressing recombinant human PDE8A1, we detected a physical association between PDE8A1 and endogenous I B␤ by an antibody array technique. The association was specific for PDE8A1 and depended on the presence of the PAS domain. Subsequent coimmunoprecipitation experiments revealed that, in addition to I B␤, other I B family members examined (p105, p100, and I B␣) also associated with PDE8A1. Furthermore, it was found that PDE8A1 competed with the p65͞p50 NF-B for I B␤ binding. Taken together, these data indicate that PDE8A1, through its PAS domain, may bind with I B proteins in a region containing their ankyrin repeats. Functionally, in vitro and in vivo experiments demonstrated that the association with I B greatly enhanced the enzyme activity of PDE8A1. However, the PDE8A1-I B association did not affect NF-B activation. The biological role of the PDE8A1-I B association remains to be elucidated.

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“…4a, b). As cyclic AMP-protein kinase A pathways are well characterized attenuators of T-cell function 20 , reduced PDE3B levels implied cAMP-mediated adaptation in T R cells to chronic TCR and IL-2 signalling. Notably, naive T cells fail to downregulate PDE3B upon TCR engagement (Fig.…”

mentioning

confidence: 99%

Foxp3-dependent programme of regulatory T-cell differentiation

Gavin

Rasmussen²,

Fontenot³

et al. 2007

Nature

1,007

867

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Regulatory CD4 1 T cells (T R cells), the development of which is critically dependent on X-linked transcription factor Foxp3 (forkhead box P3), prevent self-destructive immune responses 1 . Despite its important role, molecular and functional features conferred by Foxp3 to T R precursor cells remain unknown. It has been suggested that Foxp3 expression is required for both survival of T R precursors as well as their inability to produce interleukin (IL)-2 and independently proliferate after T-cell-receptor engagement, raising the possibility that such 'anergy' and T R suppressive capacity are intimately linked 2-4 . Here we show, by dissociating Foxp3-dependent features from those induced by the signals preceding and promoting its expression in mice, that the latter signals include several functional and transcriptional hallmarks of T R cells. Although its function is required for T R cell suppressor activity, Foxp3 to a large extent amplifies and fixes pre-established molecular features of T R cells, including anergy and dependence on paracrine IL-2. Furthermore, Foxp3 solidifies T R cell lineage stability through modification of cell surface and signalling molecules, resulting in adaptation to the signals required to induce and maintain T R cells. This adaptation includes Foxp3-dependent repression of cyclic nucleotide phosphodiesterase 3B, affecting genes responsible for T R cell homeostasis.In males, Foxp3 deficiency results in fatal early-onset systemic autoimmune disease 5 . In heterozygote Foxp3 wt/null females only one-half of T cells harbours the mutant Foxp3 allele due to random X-chromosome inactivation, whereas autoimmunity is controlled by a normal T R population expressing the Foxp3 wild-type allele. Thus, we were able to genetically mark cells actively transcribing a Foxp3 null allele, yet lacking Foxp3 protein (hereafter called T FN for Foxp3 nullexpressing T cells), through an in-frame insertion of GFP into a stop-codon-disrupted Foxp3 locus (Foxp3 gfpko ) and investigate their features in mice ( Fig. 1a; see also Supplementary Figs 1 and 2a). Female Foxp3 gfpko/wt mice were healthy, whereas male Foxp3 gfpko mice developed the same severity of autoimmunity as Foxp3 knockout (Foxp3 null ) mice 6 , resulting in death at ,4 weeks of age. Thymocyte and peripheral lymphoid organ cellularity did not differ between Foxp3 gfpko/wt and Foxp3 gfp/gfp mice, nor did the proportion of Foxp3 1 T R cells and Foxp3 2 CD4 1 T cells (data not shown). As our main focus was to characterize T FN cells in healthy Foxp3 gfpko/wt mice, analysis of autoimmune male Foxp3 gfpko mice is included as Supplementary Fig. 2.T FN cells constituted ,1-3% of mature CD4 1 thymocytes and peripheral CD4 1 T cells, indicating that Foxp3 is not required to rescue T R precursors from negative selection (Fig. 1b, c). This is consistent with a reported abundance of T-cell receptors (TCRs) characteristic of T R cells in Foxp3 null mice 7 . As ectopic expression of Foxp3 has been shown to induce a state of hyporesponsiveness in CD4 1 T cell...

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Molecular mechanisms for protein kinase A-mediated modulation of immune function

Cited by 175 publications

References 114 publications

cAMP-dependent Protein Kinase and c-Jun N-terminal Kinase Mediate Stathmin Phosphorylation for the Maintenance of Interphase Microtubules during Osmotic Stress

cAMP-dependent Protein Kinase and c-Jun N-terminal Kinase Mediate Stathmin Phosphorylation for the Maintenance of Interphase Microtubules during Osmotic Stress

Per-Arnt-Sim domain-dependent association of cAMP-phosphodiesterase 8A1 with IκB proteins

Foxp3-dependent programme of regulatory T-cell differentiation

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