Physiological Substrates of cAMP-Dependent Protein Kinase

Shabb, John B.

doi:10.1021/cr000236l

Cited by 339 publications

(328 citation statements)

References 442 publications

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“…It is involved in regulation of a vast number of cellular processes including metabolism, gene expression, proliferation, differentiation, sperm motility, and ion channel conductivity as well as learning and memory (Skalhegg & Tasken, 2000; Shabb, 2001; Kandel, 2012; Taylor et al ., 2012). The holoenzyme of PKA consists of a regulatory subunit dimer, and each regulatory subunit (R) is bound to a catalytic subunit (C).…”

Section: Introductionmentioning

confidence: 99%

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

Xie

Jin

et al. 2016

Aging Cell

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SummaryAlzheimer's disease (AD) is characterized clinically by memory loss and cognitive decline. Protein kinase A (PKA)‐CREB signaling plays a critical role in learning and memory. It is known that glucose uptake and O‐GlcNAcylation are reduced in AD brain. In this study, we found that PKA catalytic subunits (PKAcs) were posttranslationally modified by O‐linked N‐acetylglucosamine (O‐GlcNAc). O‐GlcNAcylation regulated the subcellular location of PKAcα and PKAcβ and enhanced their kinase activity. Upregulation of O‐GlcNAcylation in metabolically active rat brain slices by O‐(2‐acetamido‐2‐deoxy‐d‐glucopyranosylidenamino) N‐phenylcarbamate (PUGNAc), an inhibitor of N‐acetylglucosaminidase, increased the phosphorylation of tau at the PKA site, Ser214, but not at the non‐PKA site, Thr205. In contrast, in rat and mouse brains, downregulation of O‐GlcNAcylation caused decreases in the phosphorylation of CREB at Ser133 and of tau at Ser214, but not at Thr205. Reduction in O‐GlcNAcylation through intracerebroventricular injection of 6‐diazo‐5‐oxo‐l‐norleucine (DON), the inhibitor of glutamine fructose‐6‐phosphate amidotransferase, suppressed PKA‐CREB signaling and impaired learning and memory in mice. These results indicate that in addition to cAMP and phosphorylation, O‐GlcNAcylation is a novel mechanism that regulates PKA‐CREB signaling. Downregulation of O‐GlcNAcylation suppresses PKA‐CREB signaling and consequently causes learning and memory deficits in AD.

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Section: Introductionmentioning

confidence: 99%

O‐GlcNAcylation of protein kinase A catalytic subunits enhances its activity: a mechanism linked to learning and memory deficits in Alzheimer's disease

Xie

Jin

et al. 2016

Aging Cell

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“…Singh et al reported that laminin and fibronectin (Fn) expression induced by TGF-β1 could be down-regulated by PKA signaling blockage; however, the inhibition of PKC did not have significant effects on TGF-β1 [32] . With these observations, it was also reported that the secretion of Fn was downregulated by PPARγ activation in lung carcinoma cells, which was mediated by antagonizing the transactivating activity of CREB binding to one CRE site in the Fn promoter [33] . These results indicate a potential involvement of PKA signaling in TGF-β mediated pro-glomerulosclerosis process.…”

Section: Pparγ Agonists Suppressed Tgf-β1-induced Mcs Phenotype Altermentioning

confidence: 82%

PPARγ agonists inhibit TGF-β-PKA signaling in glomerulosclerosis

Zou

Liu

et al. 2009

Acta Pharmacol Sin

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Aim: To study the probable mechanisms of the anti-glomerulosclerosis effects induced by peroxisome proliferator-activated receptor gamma (PPARγ) agonists in rat intraglomerular mesangial cells (MCs). Methods: Cells were transfected with the pTAL-PPRE-tk-Luc + plasmid and then treated with different concentrations of PPARγ agonist, either troglitazone or telmisartan, for the indicated times. Promega luciferase assays were subsequently used for the detection of PPARγ activation. Protein expression levels were assessed by Western blot, and PepTag ® assays were used for the non-radioactive detection of protein kinase A (PKA) activity. The deposition of α-smooth muscle actin (α-SMA) and p-cyclic AMP responsive element binding protein (pCREB) were analyzed by confocal laser scanning. Results: Both troglitazone and telmisartan remarkably inhibit the PKA activation and pCREB expression that is stimulated by TGF-β. The PPARγ agonists also inhibited α-SMA and collagen IV protein expression by blocking PKA activation. Conclusion: PPARγ ligands effectively suppress the activation of MCs and the accumulation of collagen IV stimulated by TGF-β in vitro. The renal protection provided by PPARγ agonists is partly mediated via their blockade of TGF-β/PKA signaling.

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“…One of the limitations of these methods is that they would miss any substrates that are phosphorylated at sites that deviate from the derived consensus. 29,88 The other three approaches discussed here make no assumptions about the target site and thus are not restricted in this way. The large scale of the protein chip method is also an asset as it is possible to examine a significant number of candidate substrates in a single experiment.…”

Section: Discussionmentioning

confidence: 99%

“…However, not all proteins phosphorylated by PKA contain a perfect match to this consensus site, and these latter substrates would therefore be missed in this approach. 88 The bottom line is that it may be important to use multiple approaches to identify all of the relevant targets of a given protein kinase.…”

Section: Do Not Distributementioning

confidence: 99%