Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of second messenger pathways propagate inductive signals via protein-protein interactions that are phosphorylation-dependent. The second messenger, cAMP, for example, promotes cellular gene expression via the protein kinase A-mediated phosphorylation of cAMP-response element-binding protein (CREB) at Ser(133), and this modification in turn stimulates the association of CREB with the co-activator, CREB-binding protein (CBP). The solution structure of the CREB.CBP complex, using relevant interaction domains, kinase inducible domain and kinase-induced domain interacting domain, referred to as KID and KIX, respectively, shows that KID undergoes a coil to helix transition, upon binding to KIX, that stabilizes complex formation. Whether such changes occur in the context of the full-length CREB and CBP proteins, however, is unclear. Here we characterize a novel antiserum that specifically binds to the CREB. CBP complex but to neither protein individually. Epitope mapping experiments demonstrate that the CREB.CBP antiserum detects residues in KID that undergo a conformational change upon binding to KIX. The ability of this antiserum to recognize full-length CREB.CBP complexes in a phospho-(Ser(133))-dependent manner demonstrates that the structural transition observed with the isolated KID domain also occurs in the context of the full-length CREB protein. To our knowledge, this is the first report documenting formation of endogenous cellular protein-protein complexes in situ.
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PMID:Stimulus-specific interaction between activator-coactivator cognates revealed with a novel complex-specific antiserum. 1072 51

To investigate the effects of nerve growth factor (NGF) and cyclic AMP (cAMP) on the level of the nicotinic acetylcholine receptor subunit alpha3 mRNA, we used PC12h cells, PC12 cells expressing dominant-negative Ras protein, and the parental PC12 cells. PC12h cells have NGF-responsive tyrosine hydroxylase activity. Expression of dominant-negative Ras protein prevents the signaling through the Ras-mitogen-activated protein kinase cascade. The morphological changes of the parental PC12 cells in response to NGF and 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate (CPTcAMP), a cell-penetrating cAMP analogue, were similar to those of PC12h cells. NGF up-regulated the alpha3 mRNA level in PC12h cells and down-regulated the alpha3 mRNA level in the parental PC12 cells. Expression of dominant-negative Ras protein and an inhibitor of mitogen-activated protein kinase kinase inhibited the effects of NGF on alpha3 mRNA level. CPTcAMP down-regulated the alpha3 mRNA level in all three PC12 cell lines. An inhibitor of protein kinase A inhibited the CPTcAMP-induced down-regulation of alpha3 mRNA. The alpha3 mRNA down-regulation required prolonged treatment with CPTcAMP even after cAMP response element binding protein phosphorylation was decreased. Membrane depolarization with high K+ had no effect on the alpha3 mRNA level in PC12h cells. Based on these results, we propose that at least two unknown effectors regulate alpha3 mRNA levels in PC12 cells.
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PMID:Regulation of alpha3 nicotinic acetylcholine receptor subunit mRNA levels by nerve growth factor and cyclic AMP in PC12 cells. 1073 89

Protein kinase inhibitor (PKI) is a potent endogenous inhibitor of the cyclic AMP (cAMP)-dependent protein kinase (PKA). It functions by binding the free catalytic (C) subunit with a high affinity and is also known to export nuclear C subunit to the cytoplasm. The significance of these actions with respect to PKI's physiological role is not well understood. To address this, we have generated by homologous recombination mutant mice that are deficient in PKIalpha, one of the three isoforms of PKI. The mice completely lack PKI activity in skeletal muscle and, surprisingly, show decreased basal and isoproterenol-induced gene expression in muscle. Further examination revealed reduced levels of the phosphorylated (active) form of the transcription factor CREB (cAMP response element binding protein) in the knockouts. This phenomenon stems, at least in part, from lower basal PKA activity levels in the mutants, arising from a compensatory increase in the level of the RIalpha subunit of PKA. The deficit in gene induction, however, is not easily explained by current models of PKI function and suggests that PKI may play an as yet undescribed role in PKA signaling.
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PMID:Deficient gene expression in protein kinase inhibitor alpha Null mutant mice. 1077 34

Binding of cAMP to the regulatory subunit of cAMP-dependent protein kinase (PKA) is an essential step for cAMP-mediated signal transduction including phosphorylation of cAMP response element binding protein (CREB). In the present study, binding activity of PKA with cAMP and CREB phosphorylation were examined in rat focal brain ischemia induced by occlusion of the middle cerebral artery for 1.5 hours followed by various time of recirculation. Binding activity of PKA with cAMP was progressively inhibited during the acute phase of ischemia from the ischemic core to peri-ischemia area. Phosphorylated CREB-positive cells in the ischemic core revealed a significant, but transient increase in number at 3.5 hours of recirculation, followed by a rapid decrease below the control level during the subsequent period. On the other hand, in the peri-ischemia area, the number of phosphorylated CREB-positive cells showed a more marked increase as compared to that in the ischemic core, and the increase continued until 48 hours of recirculation with a tendency for gradual decline. Persistent enhancement of CREB phosphorylation may thus be closely related to the neuronal viability and neuroprotective mechanisms, whereas rapid disappearance of CREB phosphorylation following ischemic insult may clearly precede neuronal death.
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PMID:[Alteration of cAMP-mediated signal transduction in cerebral ischemia--binding activity of PKA and phosphorylation of CREB]. 1079 Nov 2

Rap1A and Rap1B are small GTPases of the Ras superfamily whose activation can be measured using a probe that interacts specifically with the GTP-bound forms of Rap1A and Rap1B. Using this procedure we demonstrate that the cyclic AMP-elevating agent forskolin activates both Rap1A and Rap1B in Rat1 cells. Whilst the protein kinase A inhibitor H89 ablated the ability of forskolin to cause cAMP response element binding protein (CREB) phosphorylation in Rat1 cells, it did not affect the ability of forskolin to activate either Rap1A and Rap1B. Forskolin differentially activated Rap1A and Rap1B isoforms in a time- and dose-dependent manner. The cAMP-specific type 4 family phosphodiesterase inhibitor rolipram potentiated the rate of activation of both Rap1A and Rap1B by forskolin challenge of Rat1 cells. Challenge of Rat1 cells with rolipram alone was able to elicit the phosphorylation of CREB but not activation of either Rap1A or Rap1B.
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PMID:Use of an activation-specific probe to show that Rap1A and Rap1B display different sensitivities to activation by forskolin in rat1 cells. 1090 23

Long-term potentiation (LTP), a cellular model for long-term memory, is generally acknowledged to consist of both a short-term phase that is characterized by a dependence on autonomous protein kinase activity, and a long-term phase that is characterized by a dependence on changes in gene expression and new protein synthesis. Similarly, long-term memory exhibits a dependence on gene expression and altered protein synthesis. Recent evidence indicates that the mitogen-activated protein kinase (MAPK) cascade plays a role in both LTP and long-term memory. The MAPK cascade has heretofore largely been studied in the context of cell division and proliferation and as such, mechanisms for the regulation of gene expression by the MAPK cascade have received considerable attention. Given the possible role of altered gene expression in the late phase of LTP and in long-term memory, we evaluated the capacity of the MAPK ERK (extracellular signal-regulated kinase) to regulate phosphorylation of the transcription factor cAMP response element binding protein (CREB) in hippocampal area CA1. Our studies indicate a critical role for the MAPK cascade in the regulation of CREB phosphorylation in the hippocampus.
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PMID:MAPK regulation of gene expression in the central nervous system. 1101 81

The cAMP response element binding protein (CREB) is a bifunctional transcription activator, exerting its effects through a constitutive activation domain (CAD) and a distinct kinase inducible domain (KID), which requires phosphorylation of Ser-133 for activity. Both CAD and phospho-KID have been proposed to recruit polymerase complexes, but this has not been directly tested. Here, we show that the entire CREB activation domain or the CAD enhanced recruitment of a complex containing TFIID, TFIIB, and RNA polymerase II to a linked promoter. The nuclear extracts used mediated protein kinase A (PKA)-inducible transcription, but phosphorylation of CRG (both of the CREB activation domains fused to the Gal4 DNA binding domain) or KID-G4 did not mediate recruitment of a complex, and mutation of the PKA site in CRG abolished transcription induction by PKA but had no effect upon recruitment. The CREB-binding protein (CBP) was not detected in the recruited complex. Our results support a model for transcription activation in which the interaction between the CREB CAD and hTAFII130 of TFIID promotes the recruitment of a polymerase complex to the promoter.
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PMID:Recruitment of an RNA polymerase II complex is mediated by the constitutive activation domain in CREB, independently of CREB phosphorylation. 1115 88

Results of the present study demonstrate that activation of the adenylyl cyclase/protein kinase A (PKA) pathway leads to increased levels of insulin-like growth factor I (IGF-I) in cultured embryonic mouse mandibular mesenchymal cells. Treatment of serum-free cultures with 10(-8) M 8-OH-DPAT (DPAT) or with 10(-5) M forskolin in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX; 10(-5) M) increased levels of IGF-I (but not IGF-II), as measured by [(125)I]protein A immunobinding. In a previous study, we showed that DPAT, forskolin, IBMX and the 5-HT(4) receptor agonist SC53116 all increased the synthesis of cyclic adenosine monophosphate (cAMP) in these cultures. Taken together, these results provide evidence that stimulation of the adenylyl cyclase/PKA pathway in embryonic mandibular mesenchymal cells positively regulates IGF-I. This is supported by the ability of the PKA inhibitor Rp-cAMPS to block increases in IGF-I caused by both DPAT and forskolin. Consistent with these results, DPAT and forskolin increased phosphorylation of the cAMP response element binding protein (CREB), which was also blocked by Rp-cAMPS. These results suggest that activation of 5-HT receptors positively coupled to the adenylyl cyclase/PKA pathway may promote transcription of IGF-I through a cAMP response element (CRE) in the IGF-I promoter. This may represent one mechanism whereby 5-HT positively regulates IGF-I expression in developing craniofacial mesenchymal cells.
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PMID:Activation of 5-HT receptors that stimulate the adenylyl cyclase pathway positively regulates IGF-I in cultured craniofacial mesenchymal cells. 1117 28

This investigation examined the effects of chronic ethanol treatment (15 days) and its withdrawal (24 h) on the expression and phosphorylation of cyclic AMP-response element-binding (CREB) protein in the rat cortex. The effects of chronic ethanol treatment and withdrawal on protein kinase A (PKA) activity and on the expression of the regulatory RII-beta- and the alpha-subtype catalytic subunits of PKA, and on the protein expression of Ca(2+)/calmodulin-dependent protein kinase IV (CaM kinase IV) and calcineurin in the rat cortex were also investigated. It was found that ethanol withdrawal but not ethanol treatment produced a significant decrease in the phosphorylated CREB (p-CREB) and CaM kinase IV protein levels in the frontal, parietal, and piriform cortex. Ethanol treatment and its withdrawal had no effect on the protein levels of total CREB in the frontal, parietal, and piriform cortex. On the other hand, ethanol treatment produced a significant reduction in the protein levels of CREB, p-CREB, and CaM kinase IV in the cingulate gyrus, and these changes reverted to normal levels during ethanol withdrawal. Total CREB protein levels were significantly higher in the cingulate gyrus during ethanol withdrawal. It was also observed that mRNA levels of CREB were significantly higher in the rat cortex during ethanol withdrawal but not during ethanol treatment. The protein levels of RII-beta- and alpha-subtype catalytic subunits of PKA and PKA activity were not modified in the rat cortex by chronic ethanol treatment and its withdrawal. Furthermore, the expression of calcineurin in the rat cortex was not altered during ethanol treatment and withdrawal. Taken together, these results suggest the possibility that decreased CREB-dependent events in the neurocircuitry of the frontal, parietal, and piriform cortex may play an important role in the phenomenon of alcohol dependence and also that decreased CREB-dependent events in the neurocircuitry of the cingulate gyrus may play a role in alcohol tolerance.
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PMID:Effects of chronic ethanol intake and its withdrawal on the expression and phosphorylation of the creb gene transcription factor in rat cortex. 1118 17

Rats exposed to a novel environment just prior to or 1-2 h, but not 4 or 6 h, before retention testing exhibited an enhanced retrieval of a one-trial inhibitory avoidance training. The bilateral intrahippocampal infusion of PD098059, an inhibitor of mitogen-activated protein kinase (MAPK), the specific upstream activator of p42 and p44 MAPKs, given 10 min before the exposure to the novel environment, blocked the enhancing effect of novelty on memory retrieval. In addition, prenovelty infusion of DL-2-amino-5-phosphonovalerate (APV), an antagonist of glutamate NMDA receptors, produced similar effects. The exposure to the novel environment is associated with an activation of p42 and p44 MAPKs and an increase in the phosphorylation state of the transcription factor cAMP response element binding protein (CREB). No changes were observed in cAMP-dependent protein kinase (PKA) activity or in alpha-CAMKII activation. Taken together, our results indicate that novelty activates hippocampal MAPKs, which are necessary, along with glutamate NMDA receptors, for the enhancing effect of novelty on retrieval.
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PMID:Novelty enhances retrieval: molecular mechanisms involved in rat hippocampus. 1129 9


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