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)

Tau protein is an integral component of paired helical filaments, a pathological feature of Alzheimer's disease. tau extracted from these filaments displays decreased electrophoretic mobility due to aberrant phosphorylation. Here we show that recombinant human tau can be phosphorylated by cAMP-dependent protein kinase resulting in decreased electrophoretic mobility. Phosphorylation of tau by cAMP-dependent protein kinase caused a 92% decrease in the maximum rate of tau-induced microtubule assembly. The sites of phosphorylation were identified by digesting phosphorylated tau with proteases, separating the peptides by reversed-phase HPLC, and analyzing the isolated peptides by liquid-secondary ion mass spectrometry and solid-phase N-terminal sequencing. Five phosphorylation sites were identified, two of which were located within microtubule binding domains. One site was previously shown to be the sole phosphorylation site for CaM kinase II; phosphorylation at this site by CaM kinase II was sufficient to cause decreased electrophoretic mobility (Steiner, B., Mandelkow, E. M., Biernat, J., Gustke, N., Meyer, H. E., Schmidt, B., Mieskes, G., Soling, H. D., Drechsel, D., Kirschner, M. W., Goedert, M., and Mandelkow, E. (1990) EMBO J. 9, 3539-3544). Thus two different second messenger-dependent protein kinases can phosphorylate tau at the same site and induce a shift in tau mobility like that seen in Alzheimer's disease.
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PMID:Phosphorylation of recombinant tau by cAMP-dependent protein kinase. Identification of phosphorylation sites and effect on microtubule assembly. 841 21

To investigate the physiological role of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) in neuronal differentiation, we transfected the cDNA of the alpha subunit of mouse CaM kinase II (CaM kinase II alpha) into PC12 cells and established clonal cell lines that constitutively express the transfected CaM kinase II alpha gene. The expression of CaM kinase II alpha was confirmed by northern blot and immunoblot analyses. Northern blot analysis showed that the gamma and delta subunits of CaM kinase II are mainly expressed in PC12 cells. Treatment of the cells with ionomycin activated CaM kinase II alpha through autophosphorylation and generation of the Ca2+/calmodulin-dependent form. It is interesting that the neurite outgrowth induced by dibutyryl cyclic AMP was inhibited in these cell lines in accordance with the activities of overexpressed CaM kinase II alpha. The activity of cyclic AMP-dependent protein kinase showed similar levels among these cell lines. These results suggest that CaM kinase II is involved in the modulation of the neurite outgrowth induced by activation of the cyclic AMP system.
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PMID:Overexpression of Ca2+/calmodulin-dependent protein kinase II inhibits neurite outgrowth of PC12 cells. 852 89

Cyclic ADP-ribose (cADPR) is generated in pancreatic islets by glucose stimulation, serving as a second messenger for Ca2+ mobilization from the endoplasmic reticulum for insulin secretion (Takasawa, S., Nata, K., Yonekura, H., and Okamoto, H. (1993) Science 259, 370-373). In the present study, we observed that the addition of calmodulin (CaM) to rat islet microsomes sensitized and activated the cADPR-mediated Ca2+ release. Inhibitors for CaM-dependent protein kinase II (CaM kinase II) completely abolished the glucose-induced insulin secretion as well as the cADPR-mediated and CaM-activated Ca2+ mobilization. Western blot analysis revealed that the microsomes contain the alpha isoform of CaM kinase II but do not contain CaM. When the active 30-kDa chymotryptic fragment of CaM kinase II was added to the microsomes, fully activated cADPR-mediated Ca2+ release was observed in the absence of CaM. These results along with available evidence strongly suggest that CaM kinase II is required to phosphorylate and activate the ryanodine-like receptor, a Ca2+ channel for cADPR as an endogenous activator, for the cADPR-mediated Ca2+ release.
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PMID:Requirement of calmodulin-dependent protein kinase II in cyclic ADP-ribose-mediated intracellular Ca2+ mobilization. 853 Apr 41

The lin-2 gene is required for the induction of the Caenorhabditis elegans vulva. Vulval development is initiated by a signal from the anchor cell that is transduced by a receptor tyrosine kinase/Ras pathway. We show that lin-2 acts in the vulval precursor cell P6.p, downstream of lin-3 EGF and upstream of let-60 ras, to allow expression of the 1 degrees cell fate. lin-2 encodes a protein of relative molecular mass 109,000 (LIN-2A) with regions of similarity to CaM kinase II and membrane-associated guanylate kinases. Mutant lin-2 transgenes designed to lack either protein kinase or guanylate kinase activity are functional, indicating that LIN-2A has a structural rather than an enzymatic role in vulval induction. Most or all identified membrane-associated guanylate kinases are components of cell junctions, including vertebrate tight junctions and arthropod septate junctions in epithelia. Thus, LIN-2A may be a component of the cell junctions of the epithelial vulval precursor cells that is required for signaling by the receptor tyrosine kinase LET-23. We propose that LIN-2A is required for the localization of one or more signal transduction proteins (such as LET-23) to either the basal membrane domain or the cell junctions, and that mislocalization of signal transduction proteins in lin-2 mutants interferes with vulval induction.
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PMID:The C. elegans vulval induction gene lin-2 encodes a member of the MAGUK family of cell junction proteins. 856 57

Activation of Ca2+/calmodulin (CaM)-dependent protein kinase II (CaM kinase II) and development of the Ca2+/CaM-independent (autonomous) form of the kinase was investigated in cultured vascular smooth muscle (VSM) cells. Within 15 s of ionomycin (1 microM) exposure 52.7 +/- 4.4% of the kinase became autonomous, a response that was partially maintained for at least 10 min. This correlated with 32P phosphorylation of CaM kinase II delta-subunits in situ and was abolished by pretreatment with the CaM kinase II inhibitor KN-93. The in situ Ca2+ dependence for generating autonomous CaM kinase II was determined in cells selectively permeabilized to Ca2+ and depleted of sarcoplasmic reticulum Ca2+ by pretreatment with thapsigargin. Analysis of the resulting curve revealed an EC50 (concentration producing 50% of maximal response) of 692 +/- 28 nM [Ca2+]i, a maximum of 68 +/- 2% of the total activity becoming autonomous reflecting nearly complete activation of CaM kinase II and a Hill slope of 3, indicating a highly cooperative process. Based on this dependence and measured [Ca2+]i responses in intact cells, increases in autonomous activity stimulated by angiotensin II, vasopressin and platelet-derived growth factor-BB (4.6-, 2-, and 1.7-fold, respectively) were unexpectedly high. In intact cells stimulated by ionomycin, the correlation between autonomous activity and [Ca2+]i resulted in a parallel curve with an EC50 of 304 +/- 23 nM [Ca2+]i. This apparent increase in Ca2+ sensitivity for generating autonomous activity in intact VSM cells was eliminated by thapsigargin pretreatment. We conclude that alteration of [Ca2+]i over a physiological range activates CaM kinase II in VSM and that this process is facilitated by release of Ca2+ from intracellular pools which initiates cooperative autophosphorylation and consequent generation of autonomous CaM kinase II activity.
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PMID:In situ Ca2+ dependence for activation of Ca2+/calmodulin-dependent protein kinase II in vascular smooth muscle cells. 857 14

We previously reported that cross-linking surface immunoglobulin (sIg) leads to induction of the transcription factor CREB in B lymphocytes through phosphorylation at Ser133, despite the lack of an increase in cAMP. Further, cAMP-raising agents fail to induce CREB Ser133 phosphorylation and CRE-dependent gene expression in these cells, which differs sharply from the situation in PC12 rat pheochromocytoma cells where CREB responds to elevation of cAMP through the activity of protein kinase A. In this study, we characterized the signal transduction pathways leading from sIg engagement to CREB activation. By using specific inhibitors for protein kinase C (PKC), Ca2+/calmodulin-dependent protein kinase II (CaM kinase II), and protein kinase A (PKA), we found that anti-Ig-induced CREB Ser133 phosphorylation depends on PKC, but does not require activation of PKA or CaM kinase II. The differential responsiveness of CREB to forskolin in PC12 cells and BAL-17 B cells may relate to the more marked elevation of cAMP in the former as opposed to the latter; however, high concentrations of dbcAMP which should readily enter B cells and artificially increase cAMP levels still failed to induce CREB Ser133 phosphorylation, even in conjunction with a phosphodiesterase inhibitor. Taken together, the cAMP/PKA pathway does not appear to be as active a contributor to CREB phosphorylation in B lymphocytes as in PC12 cells, and does not appear to be involved in sIg-induced, PKC-dependent, CREB activation.
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PMID:Signaling pathways for antigen receptor-mediated induction of transcription factor CREB in B lymphocytes. 862 May 54

The paired helical filaments (PHF) found in the brain of patients with Alzheimer disease (AD) are composed primarily of the microtubule-associated protein tau. Six isoforms of tau have been recognized and all are present in a hyperphosphorylated state in PHF. It is not known whether all tau isoforms serve equally well as substrates for various kinases. In this study we have compared the phosphorylation of human tau isoforms containing three microtubule-binding repeats and zero (tau 3), one (tau 3S), or two (tau 3L) N-terminal inserts. Four kinases (A-kinase, CK-1, CaM kinase II, GSK-3) were used for this purpose. With A-kinase, CK-1, and CaM kinase II the extent of phosphorylation was tau 3L > tau 3S > tau 3. With GSK-3 it was tau 3L approximately = tau 3S > tau 3. Tau 3 was a poor substrate for either CaM kinase II or CK-1, 32P incorporation being only 5 and 11%, respectively, of that observed by these kinases when tau 3L was the substrate. After prephosphorylation of the three tau isoforms by A-kinase, a subsequent phosphorylation by GSK-3 was stimulated several fold over tau that was not prephosphorylated. Under these conditions the extent of 32P incorporation was tau 3L > tau 3S > tau 3. Both CK-1 and GSK-3 phosphorylated ser 396 more rapidly in tau 3L compared to tau 3 or tau 3S. Our results suggest that (1) the presence of N-terminal inserts in tau isoforms are important structural determinants that modulate the specificity of several kinases; (2) the different tau isoforms may be present at different states of phosphorylation in PHF.
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PMID:Differential phosphorylation of human tau isoforms containing three repeats by several protein kinases. 863 36

Earlier studies (Hawkins, C., Xu, A., and Narayanan, N. (1994) J. Biol. Chem. 269, 31198-31206) have suggested that the Vmax of Ca2+ uptake is enhanced up to 2-fold through phosphorylation of Ser38 in the cardiac Ca2+-ATPase (SERCA2a) by calmodulin-dependent protein kinase (CaM kinase). It is difficult, however, to determine whether stimulation is caused by phosphorylation of the Ca2+-ATPase or by phosphorylation of phospholamban in cardiac microsomes. We have expressed SERCA2a in HEK-293 cells in the presence or absence of phospholamban and measured the effects on Ca2+ uptake activity of phosphorylation of microsomal proteins by CaM kinase or protein kinase A (PKA). We found no effect on the Vmax of Ca2+ uptake following phosphorylation by CaM kinase or PKA in either the presence or absence of phospholamban. The K0.5 for Ca2+ dependence of Ca2+ transport, however, was shifted following phosphorylation by either CaM kinase or PKA in those microsomes containing both SERCA2a and phospholamban, but not in those expressing only SERCA2a. Thus, we cannot confirm earlier reports of stimulation of SERCA2a activity by CaM kinase II phosphorylation of Ser38. Our studies, however, emphasize the need for adequate controls for measurement of Vmax.
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PMID:The vmax of the Ca2+-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) is not altered by Ca2+/calmodulin-dependent phosphorylation or by interaction with phospholamban. 866 32

We have recently isolated a new endogenous substrate of 70 kDa for Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) from bovine adrenal medullary cells (Yanagihara, N., Toyohira, Y., Yamamoto, H., Ohta, Y., Tsutsui, M., Miyamoto, E., and Izumi, F. (1994) Mol. Pharmacol. 46, 423-430). Here we report the sequence analysis of the 70-kDa protein and examine its phosphorylation by various protein kinases in vitro and by depolarization of the cultured cells. Protein sequencing and immunoblotting revealed that the 70-kDa protein is chromogranin A (CgA) or a closely related protein. Partially purified CgA was phosphorylated by cyclic AMP-dependent protein kinase and protein kinase C as well as CaM kinase II. Tryptic phosphopeptide mapping patterns of CgA differed among these protein kinases. In 32P-labeled bovine adrenal medullary cells, 56 mM K+ increased the phosphorylation of CgA and catecholamine secretion in similar time- and concentration-dependent manners, both of which were inhibited by 20 mM MgSO4, an inhibitor of voltage-dependent Ca2+ channels. These findings suggest that CgA serves as a substrate for several multifunctional protein kinases and that the elevation of the intracellular Ca2+ stimulates the phosphorylation of CgA associated with catecholamine secretion in cultured adrenal medullary cells.
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PMID:Phosphorylation of chromogranin A and catecholamine secretion stimulated by elevation of intracellular Ca2+ in cultured bovine adrenal medullary cells. 866 39

PHF-tau, which is phosphorylated at 10 Ser/Thr-Pro and 11 non-Ser/Thr-Pro sites, is unable to promote microtubule assembly. Phosphorylation of the non-Ser/Thr-Pro site, Ser-262, is reported to be primarily responsible for this. The identities of kinase(s) responsible for Ser-262 phosphorylation are still to be clarified. In this study we have used the monoclonal antibody 12E8, which recognizes P-Ser-262 and P-Ser-356 on tau, to survey different kinases for their abilities to phosphorylate Ser-262 on human tau 3L (tau410). In decreasing order of effectiveness we found that Ser-262 and Ser-356 phosphorylation can be catalyzed by CaM kinase II >> C-kinase >> GSK-3 approximately = A-kinase >> CK-1. CaM kinase II and C-kinase were shown to phosphorylate both Ser-262 and Ser-356. The binding of tau to taxol-stabilized microtubules was decreased by 35 and 42% after phosphorylation by CaM kinase II and C-kinase, respectively. Of the fraction of tau that bound to microtubules, about 50% was phosphorylated at Ser-262 and Ser-356. These results suggest that Ser-262 and Ser-356 are very good substrates for CaM kinase II but their phosphorylations are not sufficient to achieve maximal inhibition of tau binding to microtubules.
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PMID:Calcium/calmodulin-dependent protein kinase II phosphorylates tau at Ser-262 but only partially inhibits its binding to microtubules. 867 37


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