scholarly journals Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation

2011 ◽  
Vol 435 (3) ◽  
pp. 755-769 ◽  
Author(s):  
Kirsty F. MacKenzie ◽  
Derek A. Wallace ◽  
Elaine V. Hill ◽  
Diana F. Anthony ◽  
David J. P. Henderson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
P38 Mapk ◽  
Stress Responses ◽  
Mammalian Cells ◽  
Signal Transduction Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Intracellular Camp ◽  
Camp Accumulation ◽  
Kinase A

cAMP-specific PDE (phosphodiesterase) 4 isoforms underpin compartmentalized cAMP signalling in mammalian cells through targeting to specific signalling complexes. Their importance is apparent as PDE4 selective inhibitors exert profound anti-inflammatory effects and act as cognitive enhancers. The p38 MAPK (mitogen-activated protein kinase) signalling cascade is a key signal transduction pathway involved in the control of cellular immune, inflammatory and stress responses. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP. Such reprogramming of cAMP accumulation is recapitulated in wild-type primary macrophages, but not MK2/3-null macrophages. Phosphorylation by MK2 also triggers a conformational change in PDE4A5 that attenuates PDE4A5 interaction with proteins whose binding involves UCR2, such as DISC1 (disrupted in schizophrenia 1) and AIP (aryl hydrocarbon receptor-interacting protein), but not the UCR2-independent interacting scaffold protein β-arrestin. Long PDE4 isoforms thus provide a novel node for cross-talk between the cAMP and p38 MAPK signalling systems at the level of MK2.

Interleukin-1 alpha stimulates dopamine release by activating type II protein kinase A in PC-12 cells

1995 ◽  
Vol 269 (6) ◽  
pp. E1083-E1088
Author(s):  
A. Joseph ◽  
A. Kumar ◽  
N. A. O'Connell ◽  
R. K. Agarwal ◽  
A. R. Gwosdow
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Dopamine Release ◽  
Interleukin 1 ◽  
Intracellular Camp ◽  
Type I ◽  
Camp Accumulation ◽  
Type Ii ◽  
Pc 12 Cells ◽  
Kinase A

A recent study from this laboratory [A. R. Gwosdow, N. A. O'Connell, and A. B. Abou-Samra. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E461-E466, 1992] showed that the inflammatory mediator interleukin-1 alpha (IL-1 alpha) stimulates catecholamine release from primary cultures of rat adrenal cells. The present studies were conducted to determine whether 1) IL-1 alpha stimulates catecholamine/dopamine release from the adrenal medullary cell line PC-12 and 2) the adenosine 3',5'-cyclic monophosphate (cAMP)-protein kinase A (PKA) pathway is involved in IL-1 alpha-induced dopamine release from PC-12 cells. The results indicate that IL-1 alpha significantly (P < 0.05) elevated dopamine release after a 24-h incubation period. IL-1 alpha did not stimulate cAMP accumulation at any time period between 5 min and 2 h. In contrast, forskolin-treated cells elevated (P < 0.05) intracellular cAMP levels and increased dopamine release. Because IL-1 alpha did not affect cAMP accumulation, the effect of IL-1 alpha on PKA activity was investigated. IL-1 alpha increased (P < 0.05) PKA activity at 15 and 30 min and returned to control levels by 1 h. Forskolin also increased (P < 0.05) PKA activity. The type of PKA activated (P < 0.05) by IL-1 alpha was type II PKA. In contrast, forskolin activated (P < 0.05) type I and type II PKA. Inhibition of PKA with the PKA inhibitor H-8 blocked PKA activity and dopamine secretion by both IL-1 alpha and forskolin in PC-12 cells. These observations demonstrate that 1) IL-1 alpha stimulated dopamine release from PC-12 cells by activating PKA, 2) the mechanism of IL-1 alpha activation of PKA does not involve detectable increases in intracellular cAMP accumulation, and 3) IL-1 alpha activates type II PKA, which is used by IL-1 alpha to stimulate dopamine secretion from PC-12 cells.

scholarly journals Changes in Protein Kinase A Activity Accompany Sclerotial Development in Sclerotinia sclerotiorum

2005 ◽  
Vol 95 (4) ◽  
pp. 397-404 ◽  
Author(s):  
A. Harel ◽  
R. Gorovits ◽  
O. Yarden
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Sclerotinia Sclerotiorum ◽  
Mitogen Activated Protein Kinase ◽  
Intracellular Camp ◽  
Activity Levels ◽  
Developmental Phase ◽  
Mapk Activity ◽  
Sclerotial Development ◽  
Kinase A

Sclerotia of Sclerotinia sclerotiorum are pigmented, multihyphal structures that play a central role in the life and infection cycles of this pathogen. Sclerotial formation has been shown to be affected by increased intracellular cAMP levels. Cyclic AMP (cAMP) is a key modulator of cAMP-dependent protein kinase A (PKA) and the latter may prove to play a significant role in sclerotial development. Therefore, we monitored changes in relative PKA activity levels during sclerotial development. To do so, we first developed conditions for near-synchronous sclerotial development in culture, based on hyphal maceration and filtering. Relative PKA activity levels increased during the white-sclerotium stage in the wild-type strain, while low levels were maintained in nonsclerotium-producing mutants. Furthermore, applying caffeine, an inducer of PKA activity, resulted in increased relative PKA activity levels and was correlated with the formation of sclerotial initial-like aggregates in cultures of the non-sclerotium-producing mutants. In addition, low PKA activities were found in an antisense smk1 strain, which exhibits low extracellular-signal-regulated kinase (ERK)-type mitogen-activated protein kinase (MAPK) activity, and does not produce sclerotia. The changes in PKA activity, as well as the abundance of phosphorylated MAPKs (ERK-like as well as p38-like) that accompany sclerotial development in a distinct developmental phase manner represent a potential target for antifungal intervention.

Interleukin-1 increases protein kinase A activity by a cAMP-independent mechanism in AtT-20 cells

1994 ◽  
Vol 266 (1) ◽  
pp. E79-E84 ◽  
Author(s):  
A. R. Gwosdow ◽  
N. A. O'Connell ◽  
A. B. Abou-Samra
Keyword(s):  
Protein Kinase ◽  
Adenylate Cyclase ◽  
Protein Kinase A ◽  
Interleukin 1 ◽  
Phosphodiesterase Inhibitor ◽  
Intracellular Camp ◽  
Camp Accumulation ◽  
Acth Secretion ◽  
Intracellular Camp Accumulation ◽  
Kinase A

A recent study from this laboratory has shown that the inflammatory mediator, interleukin-1 alpha (IL-1 alpha), stimulates protein kinase A (PKA) activity and adrenocorticotropic hormone (ACTH) secretion from AtT-20 cells without any detectable increase in intracellular cAMP accumulation. The present studies were conducted to determine if cAMP is involved in IL-1 alpha activation of PKA and if PKA is responsible for IL-1 alpha-induced ACTH release from AtT-20 cells. The data are consistent with a novel mechanism of PKA activation that does not involve cAMP. Inhibition of adenylate cyclase with 2'5'-dideoxyadenosine (2'5'-DDA) did not affect IL-1 alpha-induced increases in PKA activity and ACTH secretion. In contrast, CRF-stimulated PKA activity and ACTH secretion were inhibited by 2'5'-DDA. Additional evidence was obtained using the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). IBMX did not alter IL-1 alpha-induced PKA activity or ACTH secretion, yet IBMX potentiated CRF-induced cAMP accumulation. Inhibition of PKA with the PKA inhibitor, H-8, blocked activation of PKA and ACTH secretion by both IL-1 alpha and CRF in AtT-20 cells. These observations demonstrate that 1) the mechanism of IL-1 alpha activation of PKA is independent of adenylate cyclase or cAMP and 2) PKA is used by IL-1 alpha to induce ACTH secretion from AtT-20 cells.

Regulation of spontaneous and induced resumption of meiosis in mouse oocytes by different intracellular pathways

Reproduction ◽  
2000 ◽  
pp. 377-383 ◽  
Author(s):  
L Leonardsen ◽  
A Wiersma ◽  
M Baltsen ◽  
AG Byskov ◽  
CY Andersen
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Mitogen Activated Protein Kinase ◽  
Meiotic Maturation ◽  
Mouse Oocytes ◽  
Mitogen Activated Protein ◽  
Dependent Signal ◽  
Kinase Pathway ◽  
Kinase A

The mitogen-activated protein kinase-dependent and the cAMP-protein kinase A-dependent signal transduction pathways were studied in cultured mouse oocytes during induced and spontaneous meiotic maturation. The role of the mitogen-activated protein kinase pathway was assessed using PD98059, which specifically inhibits mitogen-activated protein kinase 1 and 2 (that is, MEK1 and MEK2), which activates mitogen-activated protein kinase. The cAMP-dependent protein kinase was studied by treating oocytes with the protein kinase A inhibitor rp-cAMP. Inhibition of the mitogen-activated protein kinase pathway by PD98059 (25 micromol l(-1)) selectively inhibited the stimulatory effect on meiotic maturation by FSH and meiosis-activating sterol (that is, 4,4-dimethyl-5alpha-cholest-8,14, 24-triene-3beta-ol) in the presence of 4 mmol hypoxanthine l(-1), whereas spontaneous maturation in the absence of hypoxanthine was unaffected. This finding indicates that different signal transduction mechanisms are involved in induced and spontaneous maturation. The protein kinase A inhibitor rp-cAMP induced meiotic maturation in the presence of 4 mmol hypoxanthine l(-1), an effect that was additive to the maturation-promoting effect of FSH and meiosis-activating sterol, indicating that induced maturation also uses the cAMP-protein kinase A-dependent signal transduction pathway. In conclusion, induced and spontaneous maturation of mouse oocytes appear to use different signal transduction pathways.

scholarly journals Protein Kinase A Operates a Molecular Switch That Governs Yeast Pseudohyphal Differentiation

2002 ◽  
Vol 22 (12) ◽  
pp. 3981-3993 ◽  
Author(s):  
Xuewen Pan ◽  
Joseph Heitman
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Pathogenic Fungi ◽  
Mitogen Activated Protein Kinase ◽  
Signaling Cascades ◽  
Mitogen Activated Protein ◽  
Eukaryotic Organisms ◽  
Pseudohyphal Differentiation ◽  
Developmental Switch ◽  
Kinase A

ABSTRACT The yeast Saccharomyces cerevisiae undergoes a dimorphic filamentous transition in response to nutrient cues that is affected by both mitogen-activated protein kinase and cyclic AMP-protein kinase A signaling cascades. Here two transcriptional regulators, Flo8 and Sfl1, are shown to be the direct molecular targets of protein kinase A. Flo8 and Sfl1 antagonistically control expression of the cell adhesin Flo11 via a common promoter element. Phosphorylation by the protein kinase A catalytic subunit Tpk2 promotes Flo8 binding and activation of the Flo11 promoter and relieves repression by prohibiting dimerization and DNA binding by Sfl1. Our studies illustrate in molecular detail how protein kinase A combinatorially effects a key developmental switch. Similar mechanisms may operate in pathogenic fungi and more complex multicellular eukaryotic organisms.

scholarly journals Adenosine pretreatment attenuates angiotensin II-mediated p38 MAPK activation in a protein kinase A dependent manner

2010 ◽  
Vol 4 (5) ◽  
pp. 721-729
Author(s):  
Hamid Yaghooti ◽  
Mohsen Firoozrai ◽  
Soudabeh Fallah ◽  
Mohammad Reza Khorramizadeh
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
P38 Mapk ◽  
Inflammatory Mediators ◽  
Endothelial Permeability ◽  
Renin Angiotensin System ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Kinase A

Abstract Background: Adenosine is known as a protective and anti-inflammatory nucleoside. Angiotensin II is the main hormone of the renin-angiotensin system. It is associated with endothelial permeability, recruitment, and activation of the immune cells through induction of inflammatory mediators. Matrix metalloproteinase-9 (MMP-9) plays an important role in inflammatory processes mediated by macrophages. Objectives: Investigate whether adenosine pretreatment modulates angiotensin II-induced MMP-9 expression and activation of signaling molecules. Methods: Human monocytic U-937 cells were treated with either adenosine or angiotensin II alone or angiotensin II following a pretreatment with adenosine. Supernatants were analyzed for MMP-9 activity by zymography method. MMP-9 gene expression was analyzed using real-time PCR. Activation of inflammatory mediators IκB-α, NF-κB, JNK, p38 MAPK, and STAT3 were analyzed by a multi-target ELISA kit. Association of Protein kinase A (PKA) in adenosine effects was studied by pre-incubation with H89, a selective PKA inhibitor. Results: Treatment of the cells with angiotensin II significantly increased MMP-9 production (p <0.05). Adenosine pretreatment did not attenuate this angiotensin II effect. Angiotensin II treatment induced NF-κB, JNK and p38 activation. Pretreatment with adenosine prior to angiotensin II stimulation showed a 40% inhibitory effect on p38 induction (p <0.05). This effect was reversed by PKA inhibition. Conclusion: The present data confirmed that monocytic MMP-9 was a target gene for angiotensin II. Adenosine pretreatment did not inhibit MMP-9 increase in response to angiotensin II. However, it showed a potential inhibitory effect on angiotensin II inflammatory signaling.

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