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)

The amino acid sequences surrounding three major phosphorylation sites in rat and bovine synapsin I have been determined by employing automated gas-phase sequencing and manual Edman degradation of purified phosphopeptide fragments. Site 1 is a serine residue phosphorylated by cAMP-dependent protein kinase and by calcium/calmodulin-dependent protein kinase I. The sequence around site 1 was derived from tryptic/chymotryptic phosphopeptides and overlapping cyanogen bromide cleavage fragments. This sequence, identical in rat and bovine synapsin I, is Asn-Tyr-Leu-Arg-Arg-Arg-Leu-Ser(P)-Asp-Ser-Asn-Phe-Met. Site 1 is located at the NH2 terminus of the protein, within the collagenase-resistant head region. Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II. The sequences surrounding bovine site 2 and site 3 were derived from tryptic phosphopeptides and overlapping fragments generated by cleavage with chymotrypsin, collagenase, and endoproteinase Lys-C. The sequence around bovine site 2 is Thr-Arg-Gln-Thr-Ser(P)-Val-Ser-Gly-Gln-Ala-Pro-Pro-Lys, and the sequence around bovine site 3 is Thr-Arg-Gln-Ala-Ser(P)-Gln-Ala-Gly-Pro-Met-Pro-Arg. Sites 2 and 3 are located within the COOH-terminal, collagenase-sensitive tail region of the molecule, separated by 36 amino acids. The sequences surrounding rat site 2 and site 3 were derived from tryptic phosphopeptides. The sequence around rat site 2 is Gln-Ala-Ser(P)-Ile-Ser-Gly-Pro-Ala-Pro-Pro-Lys, and the sequence around rat site 3 is Gln-Ala-Ser(P)-Gln-Ala-Gly-Pro-Gly-Pro-Arg. Thus, the sequences surrounding the four sites that are phosphorylated by calcium/calmodulin-dependent protein kinase II, namely sites 2 and 3 in rat and bovine synapsin I, exhibit a high degree of homology.
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PMID:Amino acid sequences surrounding the cAMP-dependent and calcium/calmodulin-dependent phosphorylation sites in rat and bovine synapsin I. 311 71

Anti-peptide antibodies specific for the neuronal calcium channel alpha 1E subunit (anti-CNE1 and anti-CNE2) were produced to study the biochemical properties and subcellular distribution of the alpha 1E polypeptide from rat brain. Immunoblotting identified a single size form of 245-255 kDa which was a substrate for phosphorylation by cAMP-dependent protein kinase, protein kinase C, cGMP-dependent protein kinase, and calcium/calmodulin-dependent protein kinase II. Ligand-binding studies of alpha 1E indicate that it is not a high affinity receptor for the dihydropyridine isradipine or the peptide toxins omega-conotoxin GVIA or omega-conotoxin MVIIC at concentrations which elicit high affinity binding to other channel types in the same membrane preparation. The alpha 1E subunit is widely distributed in the brain with the most prominent immunocytochemical staining in deep midline structures such as caudate-putamen, thalamus, hypothalamus, amygdala, cerebellum, and a variety of nuclei in the ventral midbrain and brainstem. Staining is primarily in the cell soma but is also prominent in the dendritic field of a discrete subset of neurons including the mitral cells of the olfactory bulb and the distal dendritic branches of the cerebellar Purkinje cells. Our observations indicate that the 245-255 kDa alpha 1E subunit is localized in cell bodies, and in some cases in dendrites, of a broad range of central neurons and is potentially modulated by multiple second messenger-activated protein kinase.
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PMID:Biochemical properties and subcellular distribution of the neuronal class E calcium channel alpha 1 subunit. 747 5

Several neutrophil protein kinases that undergo changes in activity during Fc gamma RII activation have been investigated. These kinases include calcium/calmodulin-dependent protein kinase II (CAMPKII), mitogen-activated protein kinase (MAPK), and histone H4 protein kinase (PKH4). They are rapidly and transiently activated in a dose-dependent manner by the cross-linking of Fc gamma RII. The activation of CAMPKII but neither PKH4 nor MAPK was inhibited by treating the cells with either a tyrosine kinase inhibitor, genistein, or an intracellular calcium chelator, BAPTA/AM. The superoxide production induced by cross-linking Fc gamma RII can be inhibited partially by various protein kinase inhibitors: 33% by protein kinase C inhibitor calphostin C, 30% by CAMPKII inhibitor KN-62, and 62% by tyrosine kinase inhibitor genistein. These results indicate that cross-linking of Fc gamma RII induces multiple signaling pathways that lead to the activation of various protein kinases. The activation of these kinases may be involved directly or indirectly in the regulation of superoxide production.
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PMID:Activation of multiple protein kinases induced by cross-linking of Fc gamma RII in human neutrophils. 753 49

The microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer's disease. Both proline-dependent protein kinases (PDPKs) and non-PDPKs are involved in this hyperphosphorylation of tau. Several PDPKs can phosphorylate tau in vitro and induce Alzheimer-like epitopes to many phosphorylation-dependent antibodies. A similar induction has not been reported with non-PDPKs. In this study we have evaluated six non-PDPKs [cyclic AMP-dependent (A-kinase), calcium/phospholipid-dependent (C-kinase), casein kinase-1 (CK-1), casein kinase-2 (CK-2), calcium/calmodulin-dependent protein kinase II, and calcium/calmodulin-dependent protein kinase from rat cerebellum] for their abilities to induce Alzheimer-like epitopes on tau. Such epitopes were induced by A-kinase, C-kinase, CK-1, and CK-2, but the degree of induction achieved by CK-1 was much greater than with the other kinases. These results suggest that CK-1 may play an important role in the conversion of tau from the normal to the abnormal phosphorylation state in Alzheimer's disease.
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PMID:Phosphorylation of tau protein by casein kinase-1 converts it to an abnormal Alzheimer-like state. 753 13

The phosphorylation state of cp20, a low molecular weight membrane-associated GTP-binding protein, was previously shown to increase two- to threefold 24 h after associative conditioning. Here, cp20 is shown to be phosphorylated by protein kinase C (PKC) in vitro. Pronounced differences in activity were observed with the three major isoforms of PKC, whereas casein kinase, calcium/calmodulin-dependent protein kinase II, and cyclic AMP-dependent protein kinase produced no detectable phosphorylation of cp20. Phosphorylation of cp20 had no effect on its GTPase or GTP-binding activity but caused a translocation of cp20 from cytosol to the nuclei/mitochondrial particulate fraction. These results suggest that the increase in phosphorylation of cp20 after conditioning may be due to PKC.
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PMID:Phosphorylation of the conditioning-associated GTP-binding protein cp20 by protein kinase C. 759 25

Phospholamban is a negative regulator of the sarcoplasmic reticulum Ca(2+)-pumping ATPase. Phosphorylation of phospholamban activates the ATPase and decreases the level of cytosolic calcium. Phospholamban is phosphorylated in heart by cAMP-dependent protein kinase, cGMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II (CM-kinase-II) and in smooth muscle cells by cGMP-dependent protein kinase. In contrast to heart muscle, phospholamban is poorly phosphorylated by CM-kinase-II in extracts of rat aortic smooth muscle cells. Rat aorta phospholamban amino acid sequence was identical to dog heart. The peptide substrate specificity of CM-kinase-II from rat aorta was the same as that from rat heart. The lack of phosphorylation of rat aorta phospholamban by the CM-kinase-II appears to result from the relatively low abundance of phospholamban in smooth muscle.
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PMID:Phosphorylation of phospholamban in aortic smooth muscle cells and heart by calcium/calmodulin-dependent protein kinase II. 785 66

tau is a major component of paired helical filaments found in the neurofibrillary tangles of Alzheimer's diseased brain. However, the mechanism or mechanisms responsible for the association of tau to form these aggregates remains unknown. In this study, the role of intermolecular disulfide bonds in the formation of higher order oligomers of bovine tau and the human recombinant tau isoform T3 was examined using the chemical cross-linking agent disuccinimidylsuberate (DSS). In addition, the role of phosphorylation and oxidation state on the in vitro self-association of tau was studied using this experimental model. Stabilization of tau-tau interactions with DSS indicated that intermolecular disulfide bonds probably play a predominant role in dimer formation, but the formation of higher order oligomers of tau cannot be attributed to these bonds alone. tau-tau interactions were significantly decreased either by blocking Cys residues or by exposing the tau to a reducing (nitrogen and dithiothreitol), instead of an oxidizing, environment. tau self-association was also significantly decreased by prior phosphorylation with calcium/calmodulin-dependent protein kinase II. Phosphorylation by cyclic AMP-dependent protein kinase or dephosphorylation by alkaline phosphatase did not alter tau self-assembly. These data suggest a role for several factors that may modulate tau self-association in vivo.
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PMID:Tau self-association: stabilization with a chemical cross-linker and modulation by phosphorylation and oxidation state. 786 Nov 53

We have investigated the effects of inhibitors of protein kinases and protein phosphatases on the NMDA receptor-independent potentiation of evoked and miniature (m) excitatory postsynaptic currents (EPSCs) induced by the entry of Ca2+ via voltage-gated Ca2+ channels in hippocampal CA1 pyramidal neurons. Voltage pulse-induced potentiation was markedly attenuated when evoked in the presence of the protein kinase blockers KN-62, K-252a, or H-7. Bath application of the protein phosphatase inhibitor calyculin A converted the usual transient potentiation of both evoked and spontaneous EPSCs induced by voltage pulses into a more sustained potentiation. Similarly, the introduction of the phosphatase inhibitors microcystin LR or okadaic acid into postsynaptic cells, via patch pipettes, also resulted in a sustained increase in the amplitude of mEPSCs. We propose that entry of Ca2+ into CA1 neurons activates calcium/calmodulin-dependent protein kinase II, which leads to an enhanced responsiveness of synaptic AMPA receptor channels. The enhancement is transient, however, owing to postsynaptic phosphatase activity.
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PMID:A role for protein kinases and phosphatases in the Ca(2+)-induced enhancement of hippocampal AMPA receptor-mediated synaptic responses. 791 94

The predicted protein kinase activity of the cloned gene product of the human myotonic dystrophy locus has been experimentally verified. Affinity-purified recombinant DM protein kinase became phosphorylated itself and transphosphorylated histone H1. These activities were not present in the bacterial host cells and were exhibited by DMPK and DMPKH, recombinant proteins which contain the protein kinase domain but exhibit distinct sizes, 43 and 66 kDa, respectively. DMPKH was further purified by velocity sedimentation on sucrose gradients; both activities migrated with the recombinant protein at 41 S, consistent with discrete multimeric particles. Phosphoamino acid analysis showed that threonine (predominantly) and serine were phosphorylated in both DMPKH and histone H1. Although PKA and PKC are the known types of protein kinase with closest sequence homology to the DM protein kinase domain, purified DMPKH was inhibited by 4 mM but not 0.04-0.4 mM H7 and H8, which inhibit PKA and PKC with Ki's of 0.4-15 microM. Specific inhibitors of other classes of multifunctional serine/threonine protein kinases such as casein kinases I (CKI-7) and II (heparin) and calcium/calmodulin-dependent protein kinase II (KN-62) did not inhibit DMPKH. DMPKH did not phosphorylate membrane-associated phosphoproteins such as acetylcholine receptor or spectrin which are known to be substrates for PKA, PKC, and CKI and -II, respectively. These experimental results suggest that the active center of the recombinant human myotonic dystrophy protein kinase may have properties distinct from the well-studied classes of serine/threonine protein kinases, in contrast to predictions based upon primary structure alone.
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PMID:Phosphorylation reactions of recombinant human myotonic dystrophy protein kinase and their inhibition. 807 83

Multiple processes lead to neuronal death after ischemia, but the generation of nitric oxide (NO) is a key component in this cascade of events. The mechanisms that regulate the extent of neuronal degeneration during anoxia and NO toxicity are multifactorial. Neuronal death may be modulated by the activity of signal transduction systems that influence the toxicity of NO or its metabolic products such as cGMP. The enzyme responsible for the production of NO, nitric oxide synthase (NOS), is phosphorylated by protein kinase C (PKC), the cAMP-dependent protein kinase (PKA), and the calcium/calmodulin-dependent protein kinase II (CaM-II). We examined in primary cultured hippocampal neurons whether the protein kinases PKC, PKA, CaM-II, and cGMP-dependent protein kinase modified the toxic effects of anoxia and NO. Down-regulation of PKC activity with PMA (1 microM) increased hippocampal neuronal survival during anoxia and NO exposure from approximately 22% to 88%. Inhibitors of PKC activity (H-7, H-8, sphingosine, and staurosporine) also were neuroprotective. Down-regulation of PKC activity increased survival during anoxia even in the presence of the NOS inhibitor, N omega-methyl-L-arginine. Thus, although down-regulation of PKC activity may increase neuronal survival by decreasing NOS activity, it also is likely that PKC contributes to ischemic neuronal death by mechanisms that are independent of NOS. Inhibition of the cGMP-dependent protein kinase activity, but not the activity of the CaM-II also was neuroprotective during NO administration. In contrast to the protective effects of inhibition of PKC and the cGMP-dependent protein kinase, activation rather than inhibition of PKA increased hippocampal neuronal survival during NO exposure. These results indicate that neuronal survival during anoxia and NO exposure is linked to the modulation of PKC, PKA, and cGMP-dependent protein kinase activity but is not dependent on the CaM-II pathway. Understanding the involvement of PKC, PKA, and the cGMP-dependent protein kinase in modulating the effect of neuronal death during ischemia and NO toxicity may help in directing future therapeutic modalities for cerebrovascular disease.
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PMID:Protein kinases modulate the sensitivity of hippocampal neurons to nitric oxide toxicity and anoxia. 823 Mar 23


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