Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the sarcolemmal Na(+)-H(+) exchanger (NHE) has been implicated as a mechanism of inotropic, arrhythmogenic, antiacidotic, and hypertrophic effects of alpha(1)-adrenoceptor (AR) stimulation. Although such regulation of sarcolemmal NHE activity has been shown to be selectively mediated through the alpha(1A)-AR subtype, distal signaling mechanisms remain poorly defined. We investigated the roles of various kinase pathways in alpha(1A)-AR-mediated stimulation of sarcolemmal NHE activity in adult rat ventricular myocytes. As an index of NHE activity, trans-sarcolemmal acid efflux rate (J(H)) was determined through microepifluorescence in single cells, during recovery from intracellular acidosis in bicarbonate-free conditions. Extracellular signal-regulated kinase (ERK), p38-mitogen-activated protein kinase (MAPK), and p90(rsk) activities were indexed on the basis of analysis of their phosphorylation status. In control cells, there was no change in J(H) in response to vehicle. Phenylephrine and A61603, an alpha(1A)-AR subtype-selective agonist, increased J(H), as well as cellular ERK and p90(rsk) activities. Neither agonist affected p38 activity, which was increased with sorbitol. The MAPK kinase inhibitor PD98059 abolished phenylephrine- and A61603-induced increases in J(H) and cellular ERK and p90(rsk) activities. In contrast, the PKC inhibitor GF109203X abolished phenylephrine- and A61603-induced increases in J(H) but failed to prevent the increases in ERK and p90(rsk) activities. Our findings suggest that alpha(1A)-AR-mediated stimulation of sarcolemmal NHE activity in rat ventricular myocytes requires activation of the ERK (but not the p38) pathway of the MAPK cascade and that the ERK-mediated effect may occur via p90(rsk). Activation of PKC is also required for alpha(1A)-AR-mediated NHE stimulation, but such regulation occurs through an ERK-independent pathway.
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PMID:Roles of mitogen-activated protein kinases and protein kinase C in alpha(1A)-adrenoceptor-mediated stimulation of the sarcolemmal Na(+)-H(+) exchanger. 1066 18

Arginine vasopressin (AVP) and lysophosphatidic acid (LPA) have been shown to stimulate protein kinase C (PKC) and mitogen-activated protein (MAP) kinases and the proliferation of vascular smooth muscle cells. However, the actions of these two agents in cardiomyocytes are less well understood. To investigate the signal transduction pathways of AVP and LPA, freshly isolated adult rat cardiomyocytes were examined. Both AVP and LPA induced concentration- and time-dependent stimulation of the phosphotransferase activities of p90 ribosomal S6 kinases (RSK) and their upstream activators, extracellularly regulated kinases (ERK) 1 and 2. The activation of ERK1 and ERK2 by LPA was PKC- and phosphatidylinositol 3-kinase (PI 3-kinase)-dependent. However, AVP-induced activation of RSK2, a downstream substrate of ERK1 and ERK2, was PKC-dependent and PI 3-kinase-independent. AVP and LPA were also observed to increase the phosphotransferase activity of p70 ribosomal protein S6 kinase (p70 S6K) in a time- and concentration-dependent manner. The activation of p70 S6K by LPA and AVP was PI 3-kinase-dependent. PKC was necessary in AVP- but not in LPA-induced activation of p70 S6K. Since RSK and p70 S6K have been implicated in the regulation of translational control of protein synthesis, we concluded that AVP and LPA may stimulate the growth of cardiomyocytes through these two protein kinase cascades.
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PMID:Stimulation of 90- and 70-kDa ribosomal protein S6 kinases by arginine vasopressin and lysophosphatidic acid in rat cardiomyocytes. 1070 47

Inactive nuclear factor kappaB (NF-kappaB) complexes are retained in the cytoplasm by binding to inhibitory proteins, such as IkappaBalpha. Various stimuli lead to phosphorylation and subsequent processing of IkappaBalpha in the 26S proteasome and import of the active NF-kappaB transcription factor into the nucleus. In agreement with our previous finding that p90(rsk1) is essential for TPA-induced activation of NF-kappaB in Adenovirus 5E1-transformed Baby Rat Kidney cells, we now report that the MEK/ERK/p90(rsk1) inhibitor U0126 efficiently blocks TPA-induced IkappaBalpha processing in these cells. However, in U2OS cells, the cytokine-inducible IkappaB kinase complex (IKK) is the essential component of the TPA signal transduction pathway. Activation of the IKK complex in response to TPA is mediated by PKC-alpha, since both the PKC inhibitor GF109203 and a catalytically inactive PKC-alpha mutant inhibit activation of endogenous IKK by TPA, but not by tumor necrosis factor-alpha (TNF-alpha). We conclude that IKK is an integrator of TNF-alpha and TPA signal transduction pathways in U2OS cells.
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PMID:Protein kinase C-alpha is an upstream activator of the IkappaB kinase complex in the TPA signal transduction pathway to NF-kappaB in U2OS cells. 1115 62

Angiotensin II (Ang II) type 1 receptors (AT1Rs) activate tyrosine kinases, including Src. Whether or not tyrosine kinase activation by AT1R occurs independently of heterotrimeric G protein coupling and, if so, the cellular function of such a mechanism are unknown. To address these questions, we used an AT1aR intracellular second loop mutant, which lacks heterotrimeric G protein coupling (AT1a-i2m). Surprisingly, Ang II-induced Src activation was preserved in AT1a-i2m, which was not attenuated by inhibiting protein kinase C and Ca(2+) or by inhibiting Galpha(i) or Galpha(q) in CHO-K1 cells. By contrast, Ang II-induced Src activation was abolished in a C-terminally truncated AT1a-(1--309), where Ang II-induced inositol phosphate response was preserved. Ang II activates ERKs via a Src-Ras-dependent mechanism in AT1a-i2m. ERKs activated by AT1a-i2m phosphorylate their cytoplasmic targets, including p90(RSK), but fail to translocate into the nucleus or to cause cell proliferation. Ang II-induced nuclear translocation of ERKs by wild type AT1aR was inhibited by overexpression of nuclear exportin Crm-1, while that by AT1a-i2m was restored by leptomycin B, an inhibitor of Crm-1. In summary, while Src and ERKs are activated by Ang II even without heterotrimeric G protein coupling, the carboxyl terminus of the AT1 receptor is required for activation of Src. Interestingly, ERKs activated by heterotrimeric G protein-independent mechanisms fail to phosphorylate nuclear targets due to lack of inhibition of Crm-1-induced nuclear export of ERKs. These results suggest that heterotrimeric G protein-dependent and -independent signaling mechanisms play distinct roles in Ang II-mediated cellular responses.
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PMID:AT1 receptor mutant lacking heterotrimeric G protein coupling activates the Src-Ras-ERK pathway without nuclear translocation of ERKs. 1177 28

Pulsatile secretion of GnRH is the major regulator of gonadotropin (LH, FSH) gene expression and secretion. Recently, GnRH has been shown to rapidly stimulate the expression of early growth response protein-1 (Egr-1), a transcription factor that is essential for LHbeta gene expression in the pituitary. In this study, we examined the regulatory elements and signal transduction pathways by which GnRH regulates Egr-1 transcription. Deletion analysis of the murine Egr-1 promoter identified two regions (-370 to -342 and -116 to -73) that are critical for GnRH responsiveness in alphaT3 pituitary gonadotrope cells. The first region, which contains two serum response elements (SREs), contributed about 70-80% of GnRH inducibility, whereas the second region, which contains two SREs and one Ets binding site, conferred an additional 20-30% of activity. Mutations that abolish protein binding to these SREs and Ets binding sites completely eliminated GnRH-mediated transcriptional activation of the Egr-1 promoter. Mutation of cAMP response element reduced promoter activity by 40%. Using specific protein kinase inhibitors, GnRH stimulation of Egr-1 expression was found to be dependent on PKC/ERK pathways. In addition, GnRH activated p90 ribosomal S6 kinase, which has the potential to phosphorylate serum response factor and cAMP response element binding protein. We conclude that GnRH stimulation of Egr-1 gene expression requires several distinct SREs/Ets elements and a cAMP response element and is mediated via activation of PKC/ERK signaling pathways.
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PMID:GnRH regulates early growth response protein 1 transcription through multiple promoter elements. 1181 96

The possible involvement of the protein kinase C (PKC) pathway in transcriptional regulation of the human insulin-like growth factor-I (IGF-I) gene has been suggested. In this study, we sought to determine whether a PKC-dependent pathway is implicated in the transcriptional control, and if it is, how this occurs. Treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) caused an increase in the activity of the human IGF-I gene major promoter in HepG2 cells. A CCAAT/enhancer-binding protein (C/EBP) binding site located at +22 to +30 was bound by C/EBP beta in a TPA-dependent manner and was solely responsible for the TPA responsiveness. This increase in C/EBP beta activity occurs through transcriptional and posttranslational regulation, and the latter is mediated by activation of p90 ribosomal S6 kinase (RSK): co-expression of dominant negative RSK abolished the TPA-responsive and C/EBP beta-dependent transactivation. Also, TPA-responsive activation of GAL4-C/EBP beta chimera required the Ser residue known as the RSK target. In SK-N-MC cells, which display constitutive, high expression of IGF-I on use of the major promoter, a large amount of C/EBP beta binding was observed with the C/EBP site in the basal state. Treatment with PKC inhibitors substantially reduced the promoter activity and mRNA amounts of IGF-I, with the binding of C/EBP beta to the C/EBP site also being reduced. When the C/EBP site was disrupted, the basal promoter activity was reduced, but the reduction by the PKC inhibitor was no longer observed. These observations suggest that the increase of C/EBP beta binding to the C/EBP site, which is in part mediated via activation of RSK, can primarily explain the TPA responsiveness of the IGF-I gene promoter. The intrinsic PKC activity in SK-N-MC cells should play a major role in the constitutive, high expression of IGF-I and may therefore contribute in part to the maintenance of the tumor phenotype of the cells.
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PMID:Protein kinase C-dependent, CCAAT/enhancer-binding protein beta-mediated expression of insulin-like growth factor I gene. 1182 99

We have previously reported that lead acetate activates protein kinase Calpha (PKCalpha) and induces DNA synthesis in human 1321N1 astrocytoma cells. In this study, we investigated the ability of lead to activate the mitogen-activated protein kinase (MAPK) cascade. We found that exposure to lead acetate (1-50 microM) resulted in concentration- and time-dependent activation of MAPK (extracellular signal responsive kinase 1/2), as shown by increased phosphorylation and increased kinase activity. This effect was significantly reduced by the PKC-specific inhibitor bisindolylmaleimide (GF109203X), by down-regulation of PKC with 12-O-tetradecanoyl-phorbol 13-acetate, by a pseudosubstrate to PKCalpha, and by selective down-regulation of PKCalpha by prior lead exposure. Lead was also shown to activate MAPK kinase (MEK1/2), and this effect was mediated by PKC. Two MEK inhibitors, 2-(2'-amino-3'-methoxyphenol)-oxanaphthalen-4-one (PD98059) and 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (UO126), blocked lead-induced MAPK activation and inhibited lead-induced DNA synthesis, as measured by incorporation of [methyl-3H]thymidine into cell DNA. The 90 kDa ribosomal S6 protein kinase, p90(RSK), a substrate of MAPK, was also found to be activated by lead in a PKC- and MAPK-dependent manner. Stimulation of DNA synthesis by lead in astrocytoma cells may be of interest in light of the observed association between exposure to lead and an increased risk of astrocytomas.
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PMID:Inorganic lead activates the mitogen-activated protein kinase kinase-mitogen-activated protein kinase-p90(RSK) signaling pathway in human astrocytoma cells via a protein kinase C-dependent mechanism. 1186 86

The meiosis and fertilization of vertebrate oocyte are extensively regulated by various protein kinases. Recently, a great progress has been achieved in the studies on the molecular mechanisms of oocyte maturation, activation and fertilization. MPF and MAPK were found to be the key modulators of the cell cycle in oocyte, whose activation and inactivation result in the entry, arrest and exit of meiosis. Many protein kinases influence the meiosis by stimulating or inhibiting the activity of MPF and MAPK. Polo-like kinase activates MPF, whereas Mos initiates oocyte maturation and sustains MII arrest by activating MAPK. CaMK II down-regulates the MPF level through an ubiquitin-dependent pathway, which leads to the breakthrough of M phase arrest. Furthermore, p90(rsk) is involved in themeiosis regulation as a downstream regulator of MAPK; protein kinase C induces cortical granule exocytosis after fertilization and inhibits MAPK activity during maturation; and tyrosine protein kinase family members modulate the calcium release induced by fertilization. The cooperation of these protein kinases is essential to the development and fertilization of the oocyte.
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PMID:[Protein kinases involved in the meiotic maturation and fertilization of oocyte]. 1201 35

The gastrointestinal hormone, glucose-dependent insulinotropic polypeptide (GIP), is one of the most important regulators of insulin secretion following ingestion of a meal. GIP stimulates insulin secretion from the pancreatic beta-cell via its G protein-coupled receptor activation of adenylyl cyclase and other signal transduction pathways, but there is little known regarding subsequent protein kinase pathways that are activated. A screening technique was used to determine the relative abundance of 75 protein kinases in CHO-K1 cells expressing the GIP receptor and in two pancreatic beta-cell lines (betaTC-3 and INS-1 (832/13) cells). This information was used to identify kinases that are potentially regulated following GIP stimulation, with a focus on GIP regulation of the ERK1/2 MAPK pathway. In CHO-K1 cells, GIP induced phosphorylation of Raf-1 (Ser-259), Mek1/2 (Ser-217/Ser-221), ERK1/2 (Thr-202 and Tyr-204), and p90 RSK (Ser-380) in a concentration-dependent manner. Activation of ERK1/2 was maximal at 4 min and was cAMP-dependent protein kinase-dependent and protein kinase C-independent. Studies using a beta-cell line (INS-1 clone 832/13) corroborated these findings, and it was also demonstrated that the ERK1/2 module could be activated by GIP in the absence of glucose. Finally, we have shown that GIP regulation of the ERK1/2 module is via Rap1 but does not involve Gbetagamma subunits nor Src tyrosine kinase, and we propose that cAMP-based regulation occurs via B-Raf in both CHO-K1 and beta-cells. These results establish the importance of GIP in the cellular regulation of the ERK1/2 module and identify a role for cAMP in coupling its G protein-coupled receptors to ERK1/2 activity in pancreatic beta-cells.
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PMID:Glucose-dependent insulinotropic polypeptide activates the Raf-Mek1/2-ERK1/2 module via a cyclic AMP/cAMP-dependent protein kinase/Rap1-mediated pathway. 1213 4

3-Phosphoinositide-dependent protein kinase-1 (PDK1) plays a central role in activating the protein kinase A, G, and C subfamily. In particular, PDK1 plays an important role in regulating the Akt survival pathway by phosphorylating Akt on Thr-308. PDK1 kinase activity was thought to be constitutively active; however, recent reports suggested that its activity is regulated by binding to other proteins, such as protein kinase C-related kinase-2 (PRK2), p90 ribosomal protein S6 kinase-2 (RSK2), and heat-shock protein 90 (Hsp90). Here we report that PDK1 binds to 14-3-3 proteins in vivo and in vitro through the sequence surrounding Ser-241, a residue that is phosphorylated by itself and is critical for its kinase activity. Mutation of PDK1 to increase its binding to 14-3-3 decreased its kinase activity in vivo. By contrast, mutation of PDK1 to decrease its interaction with 14-3-3 resulted in increased PDK1 kinase activity. Moreover, incubation of wild-type PDK1 with recombinant 14-3-3 in vitro decreased its kinase activity. These data indicate that PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241.
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PMID:Regulation of kinase activity of 3-phosphoinositide-dependent protein kinase-1 by binding to 14-3-3. 1217 59


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