Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Of 21 phosphorylation sites identified in PHF-tau 11 are on ser/thr-X motifs and are probably phosphorylated by non-proline-dependent protein kinases (non-PDPKs). The identities of the non-PDPKs and how they interact to hyperphosphorylate PHF-tau are still unclear. In a previous study we have shown that the rate of phosphorylation of human tau 39 by a PDPK (GSK-3) was increased several fold if tau were first prephosphorylated by non-PDPKs (Singh et al., FEBS Lett 358: 267-272, 1995). In this study we have examined how the specificity of a non-PDPK for different sites on human tau 39 is modulated when tau is prephosphorylated by other non-PDPKs (A-kinase, C-kinase, CK-1, CaM kinase II) as well as a PDPK (GSK-3). We found that the rate of phosphorylation of tau 39 by a non-PDPK can be stimulated if tau were first prephosphorylated by other non-PDPKs. Of the four non-PDPKs only CK-1 can phosphorylate sites (thr 231, ser 396, ser 404) known to be present in PHF-tau. Further, these sites were phosphorylated more rapidly and to a greater extent by CK-1 if tau 39 were first prephosphorylated by A-kinase, CaM kinase II or GSK-3. These results suggest that the site specificities of the non-PDPKs that participate in PHF-tau hyperphosphorylation can be modulated at the substrate level by the phosphorylation state of tau.
Mol Cell Biochem 1996 Jan 26
PMID:Non-proline-dependent protein kinases phosphorylate several sites found in tau from Alzheimer disease brain. 871 28

The expression of the immediate early gene c-fos was studied at the mRNA and the protein level in cells of the pituitary tumour cell line GH3B6. The induction of c-fos mRNA as detected by Northern blot analysis was stimulated by TRH and by depolarization with KCl, both leading to a rise in cytosolic free [Ca2+] ([Ca2+]i), and also by epidermal growth factor (EGF). To assess the role of the changes in [Ca2+]i in the induction of c-fos, Ca2+ was chelated in the extracellular medium with EGTA to prohibit Ca2+ influx during stimulation, or intracellular Ca2+ stores were emptied by prolonged exposure to EGTA, a treatment which abolished all [Ca2+]i changes. In the latter case, the effect of TRH on c-fos mRNA expression was almost completely abolished, whereas EGF still caused substantial c-fos induction. Full induction of c-fos mRNA by TRH required a prolonged phase of stimulated Ca2+ influx. c-fos mRNA induction by TRH and KCl was markedly inhibited by two blockers of Ca2+/calmodulin-dependent protein kinase (CaM kinase), KN-62 and calmidazolium. In contrast, KCl induction of c-fos and the effects of KN-62 on TRH induction of c-fos were not observed in a closely related pituitary line GH4C1 in which TRH exerts its effects on immediate early genes predominantly via the protein kinase C pathway. In GH3B6 cells stimulated with TRH or KCl, enhanced FOS protein levels were detected by immunofluorescence and localized in the nucleus with confocal microscopy. Analysis by immunoblotting showed that TRH induced two protein species with apparent molecular masses of 52 and 57 kDa. In GH3B6 cells stimulated with KCl or TRH, the 52 kDa species was mainly found whereas, in the GH4C1 cells, TRH predominantly stimulated the 57 kDa species. These data show that distinct signalling pathways (CaM kinase and protein kinase C) involve Ca2+ influx to induce the transcription of the early gene c-fos, and that the resulting FOS protein species may depend on the pathways involved.
J Mol Endocrinol 1996 Jun
PMID:c-fos mRNA and FOS protein expression is induced by Ca2+ influx in GH3B6 pituitary cells. 878 81

In the corticotroph cell line AtT20, Ca2+ stimulates c-fos mRNA and nuclear c-fos protein accumulation. We show that Ca2+ stimulates transcription of a chloramphenicol-acetyl-transferase reporter gene driven by the c-fos promoter. This effect is mimicked by both constitutively active Ca2+/calmodulin-dependent protein kinase types II (CamK II) and IV (CamK IV). The effects of CamK IV are synergistic with those obtained by cAMP stimulation, whereas CamK II-dependent transcription is not further stimulated. Deletion of the distal promoter sequence revealed that CamK IV, and to a lesser extent CamK II, activate a cis-acting element(s) located between -99 and -53 bp prior to the transcription initiation site. Moreover, CamK II further stimulates transcription through the fos AP1-like element. CamK IV has a lower effect on this element but represses the serum response element. The latter observation might account for the lower transcriptional effects of CamK IV on the full length c-fos promoter.
Mol Cell Endocrinol 1996 Jun 18
PMID:Ca2+/calmodulin kinase types II and IV regulate c-fos transcription in the AtT20 corticotroph cell line. 880 32

A multifunctional Ca2+/calmodulin-dependent protein kinase (TcCaM K) was purified and characterized from the cytosol of Trypanosoma cruzi epimastigote forms. Like mammalian CaM KII, TcCaM K has a broad substrate specificity and a similar subunit composition. Western blot analysis revealed that this TcCaM K possesses two subunits of 50 and 60 kDa, which exhibited autophosphorylating activity. A panel of monoclonal and polyclonal antibodies raised against rat brain CaM KII could also recognize TcCaM K. However, experimental evidence suggests a different conformational arrangement of the TcCaM K subunits. Like its mammalian counterpart, two highly active autonomous, Ca(2+)-independent, states of TcCaM K can be isolated. These states, caused by high phosphate incorporation, differ only in their extent of Ca2+/CaM-dependence. About 15-20% of the autophosphorylated TcCaM K can be reverted using protein phosphatase 2A, and, consequently, its Ca(2+)-dependent activity is also partially restored. The situation is somewhat different when the enzyme is linked to the cytoskeleton, as we have previously shown. The membrane-bound form is present only in the native form. Activation increases its protein kinase activity from 5- to 14-fold. In this study, we provide evidence of another form of TcCaM K present in soluble fractions of the parasite that can be isolated in autonomous states. Our results suggest that autophosphorylation of membrane-bound TcCaM K may be responsible for kinase release in a Ca2+/CaM-independent state. These properties of TcCaM K may play an important role in regulating Ca(2+)-dependent processes in the parasite.
Mol Biochem Parasitol 1996 Jun
PMID:Regulation of Ca2+/calmodulin-dependent protein kinase from Trypanosoma cruzi. 881 87

Endothelin-1 (ET-1) triggers poorly understood nuclear signaling cascades that control gene expression, cell growth, and differentiation. To better understand how ET-1 regulates gene expression, we asked whether voltage-insensitive Ca2+ channels and Ca2+/calmodulin-dependent protein kinases (CaMKs) propagate signals from ET-1 receptors to the c-fos promoter in mesangial cells. Ca2+ influx through voltage-insensitive Ca2+ channels, one of the earliest postreceptor events in ET-1 signaling, mediated induction of c-fos mRNA and activation of the c-fos promoter by ET-1. A CaMK inhibitor (KN-93) blocked activation of the c-fos promoter by ET-1. Ectopic expression of CaMKII potentiated stimulation by ET-1, providing further evidence that CaMKs contribute to c-fos promoter activation by ET-1. The c-fos serum response element was necessary but not sufficient for CaMKII to activate the c-fos promoter. Activation of the c-fos promoter by ET-1 and CaMKII also required the FAP cis element, an AP-1-like sequence adjacent to the serum response element. Thus, voltage-insensitive Ca2+ channels and CaMKs apparently propagate ET-1 signals to the c-fos promoter that require multiple, interdependent cis elements. Moreover, these experiments suggest an important role for voltage-insensitive Ca2+ channels in nuclear signal transduction in nonexcitable cells.
Mol Cell Biol 1996 Oct
PMID:Voltage-insensitive Ca2+ channels and Ca2+/calmodulin-dependent protein kinases propagate signals from endothelin-1 receptors to the c-fos promoter. 881 5

Retinal cytosolic Ca2+/calmodulin-dependent protein kinase II (CaM KII) was isolated from hatched 6-wk chicken retinae by ultracentrifugation and affinity chromatography using calmodulin (CaM) and anti-CaM KII-alpha columns. Samples from different fractions were examined with SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and silver staining or immunoblotting. Comparisons were made between the final antibody affinity eluates from retina and forebrain. Silver-stained gels showed that multiple proteins were present in the antibody affinity eluates from retina, including major proteins of 178, 56, and 45 kDa and several minor proteins. Immunoblots revealed that CaM KII-alpha was present in eluates from the retina and forebrain. CaM KII-beta was present in the antibody eluate from forebrain but not retina. The latter subunit was present in the crude homogenates of the retina. Regarding the antibody eluate from retina, the possibility that the major 56 kDa protein was tubulin was ruled out, but protein tau (tau) and synapsin I were present. The presence of multiple proteins in the antibody affinity eluate indicates that these proteins were coisolated in a CaM KII-alpha-associated protein complex. The finding that protein tau and synapsin I are associated with retinal CaM KII provides further insight into the mechanisms underlying the function of the kinase in this tissue. The lack of cytosolic CaM KII-beta subunit in the antibody affinity eluate from retina is indicative of a brain region-specificity in subunit composition of the kinase.
J Mol Neurosci 1996
PMID:The Ca2+/calmodulin-dependent protein kinase II-associated protein complex isolated from chicken retina. 883 78

Tyrosine hydroxylase (TH) gene transcription rate is increased in rat adrenal medulla after administration of muscarinic agonists. In order to study this muscarinic regulation of TH gene expression in more detail, we have generated a rat pheochromocytoma PC18 cell line that stably expresses the mouse m1 muscarinic acetylcholine receptor. Treatment of this cell line, designated PC18/m1-13, with carbachol leads to rapid increases in phosphatidylinositol turnover and intracellular [Ca2+]i; these increases are totally blocked by the muscarinic antagonist atropine. Carbachol produces no changes in cAMP levels or protein kinase A activity in PC18/m1-13 cells. TH mRNA levels in PC18/m1-13 cells increase approximately 3-fold after 6 h of treatment with carbachol. This induction of TH mRNA is also completely inhibited by simultaneous treatment with atropine. Transient transfection assays using a TH gene promoter-chloramphenicol acetyltransferase (TH-CAT) construct demonstrate that sequences within the most proximal 272 bp of the TH gene 5'-flanking region are responsive to carbachol in PC18/m1-13 cells. Studies using TH-CAT constructs with site-directed mutations within the TH gene promoter indicate that the responsiveness of the promoter to carbachol is mediated primarily by the cAMP response element; however, the AP1 site also participates to a lesser extent in this response. The carbachol-mediated stimulation of TH gene promoter activity is partially inhibited by down-regulation of protein kinase C (PKC) or by treatment with the Ca2+/calmodulin-dependent protein kinase inhibitor, KN62. These results are consistent with the hypothesis that agonist occupation of m1 muscarinic receptors stimulates the TH gene via signal transduction pathways that are initiated by activation of PKC and Ca2+/calmodulin-dependent protein kinase, leading to activation of transcription factors that interact with the TH CRE and AP1 sites.
Brain Res Mol Brain Res 1996 Aug
PMID:Regulation of tyrosine hydroxylase gene expression by the m1 muscarinic acetylcholine receptor in rat pheochromocytoma cells. 884 12

We describe a method for visualizing the relative spatial distribution of autophosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) in neuronal subcompartments within hippocampal slices. The method employs a monoclonal antibody recognizing only autophosphorylated CaMKII, and an affinity-purified polyclonal rabbit antisera recognizing only nonphosphorylated CaMK II (Patton et al. (1993) Mol. Biol. Cell, 4: 159-172). 50 microns sections cut from fixed 500 microns hippocampal slices are double-labeled with these antibodies bound by secondary antibodies coupled to fluorescein and Cy3, respectively. The distribution of the two antigens in identical optical sections is recorded by dual channel confocal laser scanning microscopy (CLSM). The digital images are analyzed with the program MacPhase to determine the relative levels of staining with antibodies to phosphokinase and antibodies to nonphosphokinase in subcellular domains of neurons. Comparison of data from paired control and experimental slices reveals the spatial distributions of changes in levels of autophosphorylated CaMKII produced by pharmacological treatments. We are able to detect and spatially resolve differences in levels of autophosphorylation of CaMK II between slices subjected to Ca2+ depletion (low autophosphorylation) and slices treated with a phosphatase inhibitor (high autophosphorylation).
 ...
PMID:Visualization of autophosphorylation of Ca2+/calmodulin-dependent protein kinase II in hippocampal slices. 888 14

Type I adenylyl cyclase is a neurospecific enzyme that is stimulated by Ca2+ and calmodulin (CaM). This enzyme couples the Ca2+ and cyclic AMP (cAMP) regulatory systems in neurons, and it may play an important role for some forms of synaptic plasticity. Mutant mice lacking type I adenylyl cyclase show deficiencies in spatial memory and altered long-term potentiation (Z. Wu, S. A. Thomas, Z. Xia, E. C. Villacres, R. D. Palmiter, and D. R. Storm, Proc. Natl. Acad. Sci. USA 92:220-224, 1995). Although type I adenylyl cyclase is synergistically stimulated by Ca2+ and G-protein-coupled receptors in vivo, very little is known about mechanisms for inhibition of the enzyme. Here, we report that type I adenylyl cyclase is inhibited by CaM kinase IV in vivo. Expression of constitutively active or wild-type CaM kinase IV inhibited Ca2+ stimulation of adenylyl cyclase activity without affecting basal or forskolin-stimulated activity. Type I adenylyl cyclase has two CaM kinase IV consensus phosphorylation sequences near its CaM binding domain at Ser-545 and Ser-552. Conversion of either serine to alanine by mutagenesis abolished CaM kinase IV inhibition of adenylyl cyclase. This suggests that the activity of this enzyme may be directly inhibited by CaM kinase IV phosphorylation. Type VIII adenylyl cyclase, another enzyme stimulated by CaM, was not inhibited by CaM kinase II or IV. We propose that CaM kinase IV may function as a negative feedback regulator of type I adenylyl cyclase and that CaM kinases may regulate cAMP levels in some cells.
Mol Cell Biol 1996 Nov
PMID:Regulation of type I adenylyl cyclase by calmodulin kinase IV in vivo. 888 37

Acute aldosterone production in adrenocortical cells is highly dependent on calcium (Ca2+) and calmodulin (CaM) activation. To determine the role of calmodulin-dependent protein kinase II (CaM kinase II) in human adrenal aldosterone production, the action of KN93 (a specific CaM kinase II inhibitor) on human adrenocortical H295R cells was examined. The stimulation of aldosterone, production by angiotensin II (Ang II) and potassium (K+) were inhibited by KN93 in a concentration-dependent manner with an IC50 of approximately 0.9 and approximately 0.5 microM, respectively. Aldosterone production was also stimulated by treatment with the calcium channel activator Bay K 8644 (Bay K) (1 microM). This production was inhibited in a concentration-dependent manner by KN93 with an IC50 of between 1 and 3 microM. No inhibition by KN93 (0.3-3 microM) or by the calmodulin inhibitor calmidazolium (0.03-0.3 microM) was observed for 22R-hydroxycholesterol (22R-OHChol) stimulation of aldosterone production. Because 22R-OHChol is a substrate for the cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) and does not require active transport to the mitochondria, these results indicate that KN93 does not directly inhibit P450scc or later steps leading to aldosterone synthesis. To investigate the site of KN93 action further we examined its effect on agonists induction of steroidogenic acute regulatory (StAR) protein, which was recently shown to regulate the movement of cholesterol from the outer to the inner mitochondrial membranes. Induction of StAR protein in H295R cells by Ang II, or Bay K was not affected by co-treatment with KN93 at concentration which blocked steroidogenesis by 60-80%. These results indicate a direct role of CaM kinase II in Ang II and K+ simulation of aldosterone production and support the hypothesis that CaM kinase II may be involved in the process of cholesterol mobilization to the mitochondria.
J Steroid Biochem Mol Biol 1996 Jul
PMID:Role of calmodulin-dependent protein kinase II in the acute stimulation of aldosterone production. 890 26


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