Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been shown that cells with high affinity very late Ag (VLA)-integrins have up-regulated expression of a beta1-subunit epitope, which is detected by 15/7 mAb. In this study, we demonstrate that soluble VCAM-1 (sVCAM-1) exhibits chemotactic activity of T cells with high affinity VLA-4 against VCAM-1, such as Jurkat T cells and IL-2-dependent T cells. Moreover, we found that T cells in the synovial fluid show high basal migration in the absence of sVCAM-1, compared with peripheral blood T cells in patients with rheumatoid arthritis. Among T cells in the synovial fluid, CD45RO+ memory T cells, in response to sVCAM-1, showed a much higher than basal migratory response when compared with CD45RA+ naive cells, while no significant difference was observed between CD4+ and CD8+ T cells. The chemotactic activity of sVCAM-1 is inhibited in the presence of anti-VCAM-1 and anti-VLA-4, which interfered with the binding between VCAM-1 and VLA-4. Inhibition studies using various kinase inhibitors (C3 exoenzyme, KN62, and H7) show that Rho, Ca2+/calmodulin-dependent kinase II, and protein kinase C are involved in signal transduction in sVCAM-1-induced chemotaxis, respectively, whereas tyrosine kinase seems to play a lesser role, since genistein showed only partial inhibition of T cell chemotaxis. Western blot analysis using an anti-phospho-serine mAb (MO82) reveals that Ser82 in the vimentin is phosphorylated specifically by Ca2+/calmodulin-dependent kinase II through sVCAM-1 activation in the IL-2 dependent T cells. Collectively, by inducing migration and recruitment of T cells through several kinase activations, sVCAM-1 contributes to the development of the inflammation of synovial lesion.
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PMID:Soluble VCAM-1 induces chemotaxis of Jurkat and synovial fluid T cells bearing high affinity very late antigen-4. 979 28

Synaptic NMDA-type glutamate receptors are anchored to the second of three PDZ (PSD-95/Discs large/ZO-1) domains in the postsynaptic density (PSD) protein PSD-95. Here, we report that citron, a protein target for the activated form of the small GTP-binding protein Rho, preferentially binds the third PDZ domain of PSD-95. In GABAergic neurons from the hippocampus, citron forms a complex with PSD-95 and is concentrated at the postsynaptic side of glutamatergic synapses. Citron is expressed only at low levels in glutamatergic neurons in the hippocampus and is not detectable at synapses onto these neurons. In contrast to citron, p135 SynGAP, an abundant synaptic Ras GTPase-activating protein that can bind to all three PDZ domains of PSD-95, and Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) are concentrated postsynaptically at glutamatergic synapses on glutamatergic neurons. CaM kinase II is not expressed and p135 SynGAP is expressed in less than half of hippocampal GABAergic neurons. Segregation of citron into inhibitory neurons does not occur in other brain regions. For example, citron is expressed at high levels in most thalamic neurons, which are primarily glutamatergic and contain CaM kinase II. In several other brain regions, citron is present in a subset of neurons that can be either GABAergic or glutamatergic and can sometimes express CaM kinase II. Thus, in the hippocampus, signal transduction complexes associated with postsynaptic NMDA receptors are different in glutamatergic and GABAergic neurons and are specialized in a way that is specific to the hippocampus.
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PMID:Citron binds to PSD-95 at glutamatergic synapses on inhibitory neurons in the hippocampus. 987 Sep 42

In order to investigate the regulation of presynaptic phospholipase D (PLD) activity by calcium and G proteins, we established a permeabilization procedure for rat cortical synaptosomes using Staphylococcus aureus alpha-toxin (30-100 microg/ml). In permeabilized synaptosomes, PLD activity was significantly stimulated when the concentration of free calcium was increased from 0.1 microM to 1 microM. This activation was inhibited in the presence of KN-62 (1 microM), an inhibitor of calcium/calmodulin-dependent kinase II (CaMKII), but not by the protein kinase C inhibitor, Ro 31-8220 (1-10 microM). Synaptosomal PLD activity was also stimulated in the presence of 1 microM GTPgammaS. When Rho proteins were inhibited by pretreatment of the synaptosomes with Clostridium difficile toxin B (TcdB; 1-10 ng/ml), the effect of GTPgammaS was significantly reduced; in contrast, brefeldin A (10-100 microM), an inhibitor of ARF activation, was ineffective. Calcium stimulation of PLD was inhibited by TcdB, but GTPgammaS-dependent activation was insensitive to KN-62. We conclude that synaptosomal PLD is activated in a pathway which sequentially involves CaMKII and Rho proteins.
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PMID:Regulation of phospholipase D activity in synaptosomes permeabilized with Staphylococcus aureus alpha-toxin. 987 88

A number of guanine nucleotide exchange factors have been identified that activate Rho family GTPases, by promoting the binding of GTP to these proteins. We have recently demonstrated that lysophosphatidic acid and several other agonists stimulate phosphorylation of the Rac1-specific exchange factor Tiam1 in Swiss 3T3 fibroblasts, and that protein kinase C is involved in Tiam1 phosphorylation (Fleming, I. N., Elliott, C. M., Collard, J. G., and Exton, J. H. (1997) J. Biol. Chem. 272, 33105-33110). We now show, through manipulation of intracellular [Ca2+] and the use of protein kinase inhibitors, that both protein kinase Calpha and Ca2+/calmodulin-dependent protein kinase II are involved in the phosphorylation of Tiam1 in vivo. Furthermore, we show that Ca2+/calmodulin-dependent protein kinase II phosphorylates Tiam1 in vitro, producing an electrophoretic retardation on SDS-polyacrylamide gel electrophoresis. Significantly, phosphorylation of Tiam1 by Ca2+/calmodulin-dependent protein kinase II, but not by protein kinase C, enhanced its nucleotide exchange activity toward Rac1, by approximately 2-fold. Furthermore, Tiam1 was preferentially dephosphorylated by protein phosphatase 1 in vitro, and treatment with this phosphatase abolished the Ca2+/calmodulin-dependent protein kinase II activation of Tiam1. These data demonstrate that protein kinase Calpha and Ca2+/calmodulin-dependent protein kinase II phosphorylate Tiam1 in vivo, and that the latter kinase plays a key role in regulating the activity of this exchange factor in vitro.
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PMID:Ca2+/calmodulin-dependent protein kinase II regulates Tiam1 by reversible protein phosphorylation. 1021 59

Calponin, an F-actin-associated protein implicated in the regulation of smooth muscle contraction, is known to be phosphorylated in vitro by protein kinase C (PKC) and Ca(2+)/calmodulin dependent protein kinase II (CaM kinase II). Unphosphorylated calponin binds to F-actin and inhibits the actin-activated myosin ATPase activity; these properties are lost on phosphorylation. In the present study, we found that Rho-kinase phosphorylated basic calponin stoichiometrically in vitro. We identified the sites of phosphorylation of calponin by Rho-kinase as Thr-170, Ser-175, Thr-180, Thr-184, and Thr-259, and prepared antibodies that specifically recognized calponin phosphorylated at Thr-170 and Thr-184. We showed that the phosphorylation of calponin by Rho-kinase inhibited the binding of calponin to F-actin. Taken together, these results suggest that calponin is a substrate of Rho-kinase and that Rho-kinase regulates the interaction of calponin with F-actin.
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PMID:Identification of calponin as a novel substrate of Rho-kinase. 1087 72

The Caenorhabditis elegans sax-1 gene regulates several aspects of neuronal cell shape. sax-1 mutants have expanded cell bodies and ectopic neurites in many classes of neurons, suggesting that SAX-1 functions to restrict cell and neurite growth. The ectopic neurites in sensory neurons of sax-1 mutants resemble the defects caused by decreased sensory activity. However, the activity-dependent pathway, mediated in part by the UNC-43 calcium/calmodulin-dependent kinase II, functions in parallel with SAX-1 to suppress neurite initiation. sax-1 encodes a serine/threonine kinase in the Ndr family that is related to the Orb6 (Schizosaccharomyces pombe), Warts/Lats (Drosophila), and COT-1 (Neurospora) kinases that function in cell shape regulation. These kinases have similarity to Rho kinases but lack consensus Rho-binding domains. Dominant negative mutations in the C. elegans RhoA GTPase cause neuronal cell shape defects similar to those of sax-1 mutants, and genetic interactions between rhoA and sax-1 suggest shared functions. These results suggest that SAX-1/Ndr kinases are endogenous inhibitors of neurite initiation and cell spreading.
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PMID:Neuronal cell shape and neurite initiation are regulated by the Ndr kinase SAX-1, a member of the Orb6/COT-1/warts serine/threonine kinase family. 1098 9

Confluent endothelium serves as a selective barrier between the vascular space of blood vessels and underlying tissues. Compromised barrier function of the endothelium in response to inflammation mediators, such as thrombin, is accompanied by reversible cell rounding and interendothelial gap formation. Endothelial barrier integrity substantially depends on the cytoskeleton, which ensures actin stress fiber formation and via actomyosin-driven contraction regulates cell shape and adhesion. Recent studies have shown the sequence of events that mediate signal transduction in endothelial cells. Binding of thrombin with its receptor initiates activation of heterotrimeric G-proteins, which, in turn, entails a decrease in cAMP level in the cell, increase in intracellular Ca2+ and diacylglycerol concentration, and activation of the small G-protein Rho. Phosphorylation of myosin light chains as a result of activation of myosin light chain kinase and inactivation of myosin phosphatases stimulates stress fiber formation and triggers actomyosin contraction. In addition, thrombin-induced rearrangement in the endothelial cytoskeleton is regulated by Ca2+/calmodulin-dependent protein kinase, protein kinase C, and tyrosine protein kinases. This review focuses on presently known biochemical mechanisms of cell response to thrombin and their role in endothelial barrier dysfunction.
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PMID:Molecular mechanisms of thrombin-induced endothelial cell permeability. 1184 42

An increase in the cytosolic Ca2+ concentration is a prerequisite in activation of contractile activity of smooth muscle. The shape of the Ca2+-signal is determined by spatial distribution and kinetics of Ca2+-binding sites in the cell. The increase in cytosolic Ca2+ activates myosin light chain kinase (MLCK) which in turn phosphorylates the regulatory light chains of myosin II. This Ca2+-dependent MLC20 phosphorylation is modulated in a Ca2+-independent manner by inhibiting the constitutive active myosin light chain phosphatase mediated by the monomeric GTPase Rho and the Rho-associated kinase as well as protein kinase C or by increasing its activity through cGMP. Furthermore, the activity of MLCK may be decreased due to phosphorylation by CaM kinase II and perhaps p21 activated protein kinase. Hence, smooth muscle tone appears to be regulated by a network of activating and inactivating intracellular signaling cascades which not only show a temporal but also a spatial activation pattern.
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PMID:Ca2+-dependent and Ca2+-independent regulation of smooth muscle contraction. 1236 84

Genome project terminated and post-genome project started, one of which aim is to understand the function and its regulation mechanism(s) of the molecules in living cells. Protein phosphorylation is one of the most common reactions responsive to extracellular stimulants. It is well understood about the involvement of Rho/Rho-kinase and Cdc42/p21-activated kinase (PAK) in the functions of muscle and non-muscle cells, but in neuronal cells little or poorly is understood. This is due to poor evidences about the target molecules of Rho-kinase and PAK and its functions in neuronal cells. We have revealed using a phosphorylation site-specific antibody that PAK targets synapsin Ia at Ser603 in vitro and in neuronal cells in culture, which is recognized as CaMKII site. This is reasonable, because the 600RQAS603 around Ser603 is also consensus motif for the phosphorylation of PAK and Rho-kinase besides CaMKII. Like this, we have tried to define the target molecules of Rho-kinase in neuronal cells. In this symposium, I would present that both Rho-kinase and PAK target MARCKS at Ser159 in vitro and in neuronal cells stimulated with LPA and bradykinin, respectively. Moreover, we would address the role of phosphorylation of MARCKS at Ser159 in neuronal functions.
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PMID:[Probing of the target molecules of Rho-kinase and its function in neuronal cells]. 1472 13

Cytoplasmic Ca2+ elevation and changes in Rho GTPase activity are both known to mediate axon guidance by extracellular factors, but the causal relationship between these two events has been unclear. Here we show that direct elevation of cytoplasmic Ca2+ by extracellular application of a low concentration of ryanodine, which activated Ca2+ release from intracellular stores, upregulated Cdc42/Rac, but downregulated RhoA, in cultured cerebellar granule cells and human embryonic kidney 293T cells. Chemoattractive turning of the growth cone triggered by a gradient of ryanodine was blocked by overexpression of mutant forms of Cdc42 but not of RhoA in Xenopus spinal cord neurons. Furthermore, Ca2+-induced GTPase activity correlated with activation of protein kinase C and required a basal activity of Ca2+/calmodulin-dependent protein kinase II. Thus, Rho GTPases may mediate axon guidance by linking upstream Ca2+ signals triggered by guidance factors to downstream cytoskeletal rearrangements.
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PMID:Ca2+-dependent regulation of rho GTPases triggers turning of nerve growth cones. 1574 60


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