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)

A possible role for a protein kinase, PKN, a fatty acid-activated serine/threonine kinase with a catalytic domain homologous to the protein kinase C family and a direct target for Rho, was investigated in the pathology of Alzheimer's disease (AD) using a sensitive immunocytochemistry on postmortem human brain tissues and a kinase assay for human tau protein. The present study provides evidences by light, electron, and confocal laser microscopy that in control human brains, PKN is enriched in neurons, where the kinase is concentrated in a subset of endoplasmic reticulum (ER) and ER-derived vesicles localized to the apical compartment of juxtanuclear cytoplasm, as well as late endosomes, multivesicular bodies, Golgi bodies, secretary vesicles, and nuclei. In AD-affected neurons, PKN was redistributed to the cortical cytoplasm and neurites and was closely associated with neurofibrillary tangles (NFTs) and their major constituent, abnormally modified tau. PKN was also found in degenerative neurites within senile plaques. In addition, we report that human tau protein is directly phosphorylated by PKN both in vitro and in vivo. Thus, our results suggest a specific role for PKN in NFT formation and neurodegeneration in AD damaged neurons.
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PMID:A protein kinase, PKN, accumulates in Alzheimer neurofibrillary tangles and associated endoplasmic reticulum-derived vesicles and phosphorylates tau protein. 973 60

PKN, a fatty acid- and Rho-activated serine/threonine kinase having a catalytic domain highly homologous to protein kinase C (PKC), was cleaved at specific sites in apoptotic Jurkat and U937 cells on Fas ligation and treatment with staurosporin or etoposide, respectively. The cleavage of PKN occurred with a time course similar to that of PKCdelta, a known caspase substrate. This proteolysis was inhibited by a caspase inhibitor, acetyl-Asp-Glu-Val-Asp-aldehyde. The cleavage fragments were generated in vitro from PKN by treatment with recombinant caspase-3. Site-directed mutagenesis of specific aspartate residues prevented the appearance of these fragments. These results indicate that PKN is cleaved by caspase-3 or related protease during apoptosis. The major proteolysis took place between the amino-terminal regulatory domain and the carboxyl-terminal catalytic domain, and it generated a constitutively active kinase fragment. The cleavage of PKN may contribute to signal transduction, eventually leading to apoptosis.
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PMID:Proteolytic activation of PKN by caspase-3 or related protease during apoptosis. 975 6

Phosphoinositide-dependent protein kinase-1 (PDK1) is a recently identified serine/threonine kinase that phosphorylates and activates Akt and p70(S6K), two downstream kinases of phosphatidylinositol 3-kinase. To further study the potential role of PDK1, we have screened a mouse liver cDNA library and identified a cDNA encoding the enzyme. The predicted mouse PDK1 (mPDK1) protein contained 559 amino acids and a COOH-terminal pleckstrin homology domain. A 7-kilobase mPDK1 mRNA was broadly expressed in mouse tissues and in embryonic cells. In the testis, a high level expression of a tissue-specific 2-kilobase transcript was also detected. Anti-mPDK1 antibody recognized multiple proteins in mouse tissues with molecular masses ranging from 60 to 180 kDa. mPDK1 phosphorylated the conserved threonine residue (Thr402) in the activation loop of protein kinase C-zeta and activated the enzyme in vitro and in cells. Our findings suggest that there may be different isoforms of mPDK1 and that the protein is an upstream kinase that activates divergent pathways downstream of phosphatidylinositol 3-kinase.
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PMID:Primary structure, tissue distribution, and expression of mouse phosphoinositide-dependent protein kinase-1, a protein kinase that phosphorylates and activates protein kinase Czeta. 1007 13

Protein kinase B (PKB), also known as Akt or RAC-PK, is a serine/threonine kinase that can be activated by growth factors via phosphatidylinositol 3-kinase. In this article we show that PKCzeta but not PKCalpha and PKCdelta can co-immunoprecipitate PKB from CHO cell lysates. Association of PKB with PKCzeta was also found in COS-1 cells transiently expressing PKB and PKCzeta, and moreover we found that this association is mediated by the AH domain of PKB. Stimulation of COS-1 cells with platelet-derived growth factor (PDGF) resulted in a decrease in the PKB-PKCzeta interaction. The use of kinase-inactive mutants of both kinases revealed that dissociation of the complex depends upon PKB activity. Analysis of the activities of the interacting kinases showed that PDGF-induced activation of PKCzeta was not affected by co-expression of PKB. However, both PDGF- and p110-CAAX-induced activation of PKB were significantly abolished in cells co-expressing PKCzeta. In contrast, co-expression of a kinase-dead PKCzeta mutant showed an increased induction of PKB activity upon PDGF treatment. Downstream signaling of PKB, such as the inhibition of glycogen synthase kinase-3, was also reduced by co-expression of PKCzeta. A clear inhibitory effect of PKCzeta was found on the constitutively active double PKB mutant (T308D/S473D). In summary, our results demonstrate that PKB interacts with PKCzeta in vivo and that PKCzeta acts as a negative regulator of PKB.
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PMID:Protein kinase Czeta is a negative regulator of protein kinase B activity. 1008 94

Serine/threonine phosphorylation of insulin receptor substrate 1 (IRS-1) has been implicated as a negative regulator of insulin signaling. Prior studies have indicated that this negative regulation by protein kinase C involves the mitogen-activated protein kinase and phosphorylation of serine 612 in IRS-1. In the present studies, the negative regulation by platelet-derived growth factor (PDGF) was compared with that induced by endothelin-1, an activator of protein kinase C. In contrast to endothelin-1, the inhibitory effects of PDGF did not require mitogen-activated protein kinase or the phosphorylation of serine 612. Instead, three other serines in the phosphorylation domain of IRS-1 (serines 632, 662, and 731) were required for the negative regulation by PDGF. In addition, the PDGF-activated serine/threonine kinase called Akt was found to inhibit insulin signaling. Moreover, this inhibition required the same IRS-1 serine residues as the inhibition by PDGF. Finally, the negative regulatory effects of PDGF and Akt were inhibited by rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), one of the downstream targets of Akt. These studies implicate the phosphatidylinositol 3-kinase/Akt kinase cascade as an additional negative regulatory pathway for the insulin signaling cascade.
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PMID:Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway. 1009 13

The cellular integrity and response to hypoosmotic conditions in the yeast Saccharomyces cerevisiae are ensured by a MAP kinase signal transduction pathway mediated by the yeast homolog of mammalian protein kinase C. Bck1p functions as the MAP kinase kinase kinase of this pathway. Here we report on the cloning and analysis of the BCK1 homolog from the milk yeast Kluyveromyces lactis (KlBCK1). The deduced protein sequences display three highly conserved domains with the serine/threonine kinase domain containing 89 % identical amino acid residues. Interestingly, a region identified in KlBck1p as a putative SAM domain, mediating protein-protein interactions, is also conserved in ScBck1p. Yet, two-hybrid analyses indicate that this region may not be involved in dimerization of KlBck1p in contrast to its S. cerevisiae counterpart. Expression of KlBCK1 fully complements the defects in a Scbck1 null mutant and is capable of activating the pathway as indicated by a reporter system based on the transcription factor Rlm1p. However, deletion from the haploid K. lactis genome does not result in a loss of cellular integrity under a variety of conditions tested. Thus, despite the functional conservation in this component of the MAP kinase pathway in both yeast, cellular integrity in K. lactis may depend at least in part on different signalling mechanisms when compared with S. cerevisiae.
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PMID:Characterization of KLBCK1, encoding a MAP kinase kinase kinase of Kluyveromyces lactis. 1032 46

Stimulation of phospholipase D (PLD) by membrane receptors is now recognized as a major signal transduction pathway involved in diverse cellular functions. Rho proteins control receptor signaling to PLD, and these GTPases have been shown to directly stimulate purified recombinant PLD1 enzymes in vitro. Here we report that stimulation of PLD activity, measured in the presence of phosphatidylinositol 4,5-bisphosphate, by RhoA in membranes of HEK-293 cells expressing the m3 muscarinic acetylcholine receptor (mAChR) is phosphorylation-dependent. Therefore, the possible involvement of the RhoA-stimulated serine/threonine kinase, Rho-kinase, was investigated. Overexpression of Rho-kinase and constitutively active Rho-kinase (Rho-kinase-CAT) but not of kinase-deficient Rho-kinase-CAT markedly increased m3 mAChR-mediated but not protein kinase C-mediated PLD stimulation, similar to overexpression of RhoA. Expression of the Rho-inactivating C3 transferase abrogated the stimulatory effect of wild-type Rho-kinase, but not of Rho-kinase-CAT. Recombinant Rho-kinase-CAT mimicked the phosphorylation-dependent PLD stimulation by RhoA in HEK-293 cell membranes. Finally, the Rho-kinase inhibitor HA-1077 largely inhibited RhoA-induced PLD stimulation in membranes as well as PLD stimulation by the m3 mAChR but not by protein kinase C in intact HEK-293 cells. We conclude that Rho-kinase is involved in Rho-dependent PLD stimulation by the G protein-coupled m3 mAChR in HEK-293 cells. Thus, our findings identify Rho-kinase as a novel player in the receptor-controlled PLD signaling pathway.
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PMID:A role for rho-kinase in rho-controlled phospholipase D stimulation by the m3 muscarinic acetylcholine receptor. 1032 58

We have previously shown that protein kinase C-beta (PKC-beta) is required for activation of tyrosinase (Park, H. Y., Russakovsky, V., Ohno, S., and Gilchrest, B. A. (1993) J. Biol. Chem. 268, 11742-11749), the rate-limiting enzyme in melanogenesis. We now examine its mechanism of activation in human melanocytes. In vivo phosphorylation experiments revealed that tyrosinase is phosphorylated through the PKC-dependent pathway and that introduction of PKC-beta into nonpigmented human melanoma cells lacking PKC-beta lead to the phosphorylation and activation of tyrosinase. Preincubation of intact melanosomes with purified active PKC-beta in vitro increased tyrosinase activity 3-fold. By immunoelectron microscopy, PKC-beta but not PKC-alpha was closely associated with tyrosinase on the outer surface of melanosomes. Western blot analysis confirmed the association of PKC-beta with melanosomes. Only the cytoplasmic (extra-melanosomal) domain of tyrosinase, which contains two serines but no threonines, was phosphorylated by the serine/threonine kinase PKC-beta. These two serines at positions 505 and 509 both are present in the C-terminal peptide generated by trypsin digestion of tyrosinase. Co-migration experiments comparing synthetic peptide standards of all three possible phosphorylated tryptic peptides, a diphosphopeptide and two monophosphopeptides, to tyrosinase-phosphorylated in intact melanocytes by PKC-beta and then subjected to trypsin digestion revealed that both serine residues are phosphorylated by PKC-beta. We conclude that PKC-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome-associated protein.
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PMID:Protein kinase C-beta activates tyrosinase by phosphorylating serine residues in its cytoplasmic domain. 1034 9

Angiotensin (A) II is a potent constrictor as well as growth stimulant of vascular smooth muscle cell caused by activation of AT1 receptor signal transduction systems. There are two major signal systems of AT1 receptor: one leads to an increase in cytosolic free calcium levels causing smooth muscle contraction which may result in high blood pressure, and the other leads to smooth muscle proliferation and inflammation which may result in atherosclerosis. AT1 receptor activation induces phosphinositide hydrolysis by phospholipase C and creates an inositol phosphate, which release calcium from cytosolic calcium pools. Cytosolic calcium can also be elevated by activation of calcium channel via a link between AT1 receptor and a G protein. Protein phosphorylation triggered by AT1 receptor is important for cell growth, in which tyrosine kinase, serine/threonine kinase and protein kinase C are involved. Free radicals are generated by NADH/NADPH oxidase in response to AT1 receptor activation, causing expression of genes leading to atherosclerosis. On the other hand, activation of AT2 receptor is shown to play a role of lowering blood pressure. Some phosphatases and NO/cyclic GMP would be involved in the mechanism. In renal vasculature, endothelium dependent epoxygenase products are synthesized by AT2 receptor stimulation causing vasorelaxation. In summary, AT1 receptor signals are vasopressive and evoke atherosclerosis, whereas AT2 receptor signals may possibly be vasodilatory.
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PMID:[Signal transduction systems of angiotensin II receptors]. 1036 37

The Akt serine/threonine kinase is required for the survival of many cell types and for transformation of hematopoietic cells by the BCR/ABL oncogenic tyrosine kinase. Analysis of the potential mechanisms whereby Akt promotes survival of hematopoietic cells revealed that it induced the activity of plasma membrane and mitochondrial Raf-1 in a Ras-independent, but PKC-dependent manner. Inhibition of plasma membrane Raf-1-dependent mitogen-activated protein kinase activity had no effect on the enhanced survival of cells expressing Akt. By contrast, suppression of mitochondrial Raf-1 enzymatic activity by expression of a mitochondria-targeted Raf-1 dominant-negative mutant rendered Akt-expressing cells susceptible to apoptosis induced by growth factor deprivation and was accompanied by inhibition of BAD, but not mitogen-activated protein kinase, phosphorylation. Together, these data indicate that PKC-dependent activation of Raf-1 plays an important role in Akt-dependent antiapoptotic effects.
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PMID:Activation of mitochondrial Raf-1 is involved in the antiapoptotic effects of Akt. 1038 38


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