scholarly journals CNOT1 mediates phosphorylation via Protein kinase A on the circadian clock

2019 ◽  
Author(s):  
Yunfeng Zhang ◽  
Haitang Qin ◽  
Yongjie Feng ◽  
Peng Gao ◽  
Yingbin Zhong ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Circadian Clock ◽  
Protein Kinase A ◽  
Feedback Loop ◽  
Critical Role ◽  
Positive Element ◽  
Endogenous Protein ◽  
Genes Encoding ◽  
Genetic Deletion ◽  
Kinase A

AbstractAt the core of the mammalian circadian feedback loop, CLOCK (NPAS2)-BMAL1 is the positive element to activate transcription of downstream genes encoding the negative elements PERs and CRYs. Here we show that CNOT1 associates with both CLOCK and BMAL1, promotes their phosphorylation and increases their protein stability, and in turn inhibits the transcriptional activity of CLOCK-BMAL1. Expression of either CLOCK, BMAL1 or CNOT1 could interact with endogenous Protein Kinase A (PKA) as assessed by co-immunoprecipitation (Co-IP) and kinase assays. PKA could phosphorylate CLOCK and BMAL1 and this was promoted by CNOT1. Genetic deletion of PKA-Cα by CRISPR-Cas9 results in a longer period of the circadian rhythm; while overexpression of PKA-Cα induces a shorter period. Furthermore, we demonstrate that CNOT1 associates with CLOCK and BMAL1 in the mouse liver and promotes their phosphorylation. PER2, but not CRY2, is also a PKA target. Our results suggest that CNOT1 and PKA play a critical role in the mammalian circadian clock, revealing a conserved function in eukaryotic circadian regulations.

patched overexpression alters wing disc size and pattern: transcriptional and post-transcriptional effects on hedgehog targets

Development ◽  
1995 ◽  
Vol 121 (12) ◽  
pp. 4161-4170 ◽  
Author(s):  
R.L. Johnson ◽  
J.K. Grenier ◽  
M.P. Scott
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Target Genes ◽  
Critical Role ◽  
Wing Disc ◽  
Wing Vein ◽  
Anterior Compartment ◽  
Protein Levels ◽  
Anterior Posterior ◽  
Kinase A

The membrane protein, Patched, plays a critical role in patterning embryonic and imaginal tissues in Drosophila. patched constitutively inactivates the transcription of target genes such as wingless, decapentaplegic, and patched itself. The secreted protein, Hedgehog, induces transcription of target genes by opposing the Patched signaling pathway. Using the Gal4 UAS system we have overexpressed patched in wing imaginal discs and found that high Patched levels, expressed in either normal or ectopic patterns, result in loss of wing vein patterning in both compartments centering at the anterior/posterior border. In addition, patched inhibits the formation of the mechanosensory neurons, the campaniform sensilla, in the wing blade. The patched wing vein phenotype is modulated by mutations in hedgehog and cubitus interruptus (ci). Patched overexpression inhibits transcription of patched and decapentaplegic and post-transcriptionally decreases the amount of Ci protein at the anterior/posterior boundary. In hedgehogMrt wing discs, which express ectopic hedgehog, Ci levels are correspondingly elevated, suggesting that hedgehog relieves patched repression of Ci accumulation. Protein kinase A also regulates Ci; protein kinase A mutant clones in the anterior compartment have increased levels of Ci protein. Thus patched influences wing disc patterning by decreasing Ci protein levels and inactivating hedgehog target genes in the anterior compartment.

scholarly journals Genes encoding catalytic subunits of protein kinase a and risk of spina bifida

2005 ◽  
Vol 73 (9) ◽  
pp. 591-596 ◽  
Author(s):  
Huiping Zhu ◽  
Wei Lu ◽  
Cecile Laurent ◽  
Gary M. Shaw ◽  
Edward J. Lammer ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Spina Bifida ◽  
Protein Kinase A ◽  
Catalytic Subunits ◽  
Genes Encoding ◽  
Kinase A

Inhibition of protein kinase A phase delays the mammalian circadian clock

1999 ◽  
Vol 835 (2) ◽  
pp. 350-353 ◽  
Author(s):  
Jennifer M. Lee ◽  
Kathryn M. Schak ◽  
Mary E. Harrington
Keyword(s):  
Protein Kinase ◽  
Circadian Clock ◽  
Protein Kinase A ◽  
Kinase A

scholarly journals Pde1 Phosphodiesterase Modulates Cyclic AMP Levels through a Protein Kinase A-Mediated Negative Feedback Loop in Cryptococcus neoformans

2005 ◽  
Vol 4 (12) ◽  
pp. 1971-1981 ◽  
Author(s):  
Julie K. Hicks ◽  
Yong-Sun Bahn ◽  
Joseph Heitman
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Protein Kinase A ◽  
Cryptococcus Neoformans ◽  
Mutant Strain ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
Camp Levels ◽  
Kinase A

ABSTRACT The virulence of the human pathogenic fungus Cryptococcus neoformans is regulated by a cyclic AMP (cAMP)-dependent protein kinase A (PKA) signaling cascade that promotes mating and the production of melanin and capsule. In this study, genes encoding homologs of the Saccharomyces cerevisiae low- and high-affinity phosphodiesterases, PDE1 and PDE2, respectively, were deleted in serotype A strains of C. neoformans. The resulting mutants exhibited moderately elevated levels of melanin and capsule production relative to the wild type. Epistasis experiments indicate that Pde1 functions downstream of the Gα subunit Gpa1, which initiates cAMP-dependent signaling in response to an extracellular signal. Previous work has shown that the PKA catalytic subunit Pka1 governs cAMP levels via a negative feedback loop. Here we show that a pde1Δ pka1Δ mutant strain exhibits cAMP levels that are dramatically increased (∼15-fold) relative to those in a pka1Δ single mutant strain and that a site-directed mutation in a consensus PKA phosphorylation site reduces Pde1 function. These data provide evidence that fluctuations in cAMP levels are modulated by both Pka1-dependent regulation of Pde1 and another target that comprise a robust negative feedback loop to tightly constrain intracellular cAMP levels.

scholarly journals Wnt signaling and PKA control Nodal expression and left-right determination in the chick embryo

Development ◽  
2001 ◽  
Vol 128 (16) ◽  
pp. 3189-3195 ◽  
Author(s):  
Concepción Rodríguez-Esteban ◽  
Javier Capdevila ◽  
Yasuhiko Kawakami ◽  
Juan Carlos Izpisúa Belmonte
Keyword(s):  
Protein Kinase ◽  
Chick Embryo ◽  
Wnt Signaling ◽  
Protein Kinase A ◽  
Adhesion Protein ◽  
Fibroblast Growth Factor 8 ◽  
Endogenous Protein ◽  
Asymmetric Pattern ◽  
The Right ◽  
Kinase A

Expression of the Nodal gene, which encodes a member of the TGFβ superfamily of secreted factors, localizes to the left side of the developing embryo in all vertebrates examined so far. This asymmetric pattern correlates with normal development of the left-right axis. We now show that the Wnt and PKA signaling pathways control left-right determination in the chick embryo through Nodal. A Wnt/β-catenin pathway controlsNodal expression in and around Hensen's node, without affecting the upstream regulators Sonic hedgehog, Car and Fibroblast Growth Factor 8. Transcription of Nodal is also positively regulated by a protein kinase A-dependent pathway. Both the adhesion protein N-cadherin and PKI (an endogenous protein kinase A inhibitor) are localized to the right side of the node and may contribute to restrict Nodal activation by Wnt signaling and PKA to the left side of the node.

Endogenous protein kinase A inhibitor (PKI?) modulates synaptic activity

1998 ◽  
Vol 53 (3) ◽  
pp. 269-278 ◽  
Author(s):  
Luis de Lecea ◽  
Jos� R. Criado ◽  
Santiago Rivera ◽  
Wei Wen ◽  
Eduardo Soriano ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Synaptic Activity ◽  
Endogenous Protein ◽  
Kinase A

scholarly journals Protein Kinase A Contributes to the Negative Control of Snf1 Protein Kinase in Saccharomyces cerevisiae

2011 ◽  
Vol 11 (2) ◽  
pp. 119-128 ◽  
Author(s):  
LaKisha Barrett ◽  
Marianna Orlova ◽  
Marcin Maziarz ◽  
Sergei Kuchin
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Slow Growth ◽  
Negative Control ◽  
Regulatory Subunit ◽  
Checkpoint Control ◽  
Glucose Limitation ◽  
Genes Encoding ◽  
Kinase A

ABSTRACT Snf1 protein kinase regulates responses to glucose limitation and other stresses. Snf1 activation requires phosphorylation of its T-loop threonine by partially redundant upstream kinases (Sak1, Tos3, and Elm1). Under favorable conditions, Snf1 is turned off by Reg1-Glc7 protein phosphatase. The reg1 mutation causes increased Snf1 activation and slow growth. To identify new components of the Snf1 pathway, we searched for mutations that, like snf1 , suppress reg1 for the slow-growth phenotype. In addition to mutations in genes encoding known pathway components ( SNF1 , SNF4 , and SAK1 ), we recovered “fast” mutations, designated fst1 and fst2 . Unusual morphology of the mutants in the Σ1278b strains employed here helped us identify fst1 and fst2 as mutations in the RasGAP genes IRA1 and IRA2 . Cells lacking Ira1, Ira2, or Bcy1, the negative regulatory subunit of cyclic AMP (cAMP)-dependent protein kinase A (PKA), exhibited reduced Snf1 pathway activation. Conversely, Snf1 activation was elevated in cells lacking the Gpr1 sugar receptor, which contributes to PKA signaling. We show that the Snf1-activating kinase Sak1 is phosphorylated in vivo on a conserved serine (Ser1074) within an ideal PKA motif. However, this phosphorylation alone appears to play only a modest role in regulation, and Sak1 is not the only relevant target of the PKA pathway. Collectively, our results suggest that PKA, which integrates multiple regulatory inputs, could contribute to Snf1 regulation under various conditions via a complex mechanism. Our results also support the view that, like its mammalian counterpart, AMP-activated protein kinase (AMPK), yeast Snf1 participates in metabolic checkpoint control that coordinates growth with nutrient availability.

scholarly journals Differential Effects of Protein Kinase A on Ras Effector Pathways

1998 ◽  
Vol 18 (7) ◽  
pp. 3718-3726 ◽  
Author(s):  
Marsha J. Miller ◽  
Lise Rioux ◽  
Gregory V. Prendergast ◽  
Sarah Cannon ◽  
Michael A. White ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Thyroid Cells ◽  
Mapk Phosphorylation ◽  
Differential Effects ◽  
Effector Pathways ◽  
Rat Thyroid ◽  
Kinase A

ABSTRACT Ras mutants with the ability to interact with different effectors have played a critical role in the identification of Ras-dependent signaling pathways. We used two mutants, RasS35 and RasG37, which differ in their ability to bind Raf-1, to examine Ras-dependent signaling in thyroid epithelial cells. Wistar rat thyroid cells are dependent upon thyrotropin (TSH) for growth. Although TSH-stimulated mitogenesis requires Ras, TSH activates protein kinase A (PKA) and downregulates signaling through Raf and the mitogen-activated protein kinase (MAPK) cascade. Cells expressing RasS35, a mutant which binds Raf, or RasG37, a mutant which binds RalGDS, exhibited TSH-independent proliferation. RasS35stimulated morphological transformation and anchorage-independent growth. RasG37 stimulated proliferation but not transformation as measured by these indices. TSH exerted markedly different effects on the Ras mutants and transiently repressed MAPK phosphorylation in RasS35-expressing cells. In contrast, TSH stimulated MAPK phosphorylation and growth in cells expressing RasG37. The Ras mutants, in turn, exerted differential effects on TSH signaling. RasS35 abolished TSH-stimulated changes in cell morphology and thyroglobulin expression, while RasG37 had no effect on these activities. Together, the data indicate that cross talk between Ras and PKA discriminates between distinct Ras effector pathways.

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