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)

Apolipoprotein A-I (apoA-I) induces the translocation of newly synthesized cholesterol as well as caveolin-1 to the cytosolic lipid-protein particle (CLPP) fraction in astrocytes before its appearance in high density lipoprotein generated in the medium (Ito, J., Y. Nagayasu, K. Kato, R. Sato, and S. Yokoyama. 2002. Apolipoprotein A-I induces translocation of cholesterol, phospholipid, and caveolin-1 to cytosol in rat astrocytes. J. Biol. Chem. 277: 7929-7935). We here report the association of signal-related molecules with CLPP. ApoA-I induces rapid translocation of protein kinase Calpha to the CLPP fraction and its phosphorylation in astrocytes. ApoA-I also induces the translocation of phospholipase Cgamma to CLPP. Diacylglyceride (DG) production is increased by apoA-I in the cells, with a maximum at 5 min after the stimulation, and the increase takes place also in the CLPP fraction. An inhibitor of receptor-coupled phospholipase C, U73122, inhibited all the apoA-I-induced events, such as DG production, cholesterol translocation to the cytosol, release of cholesterol, and translocation of protein kinase Calpha into the CLPP fraction. CLPP may thus be involved in the apoA-I-initiated signal transduction in astrocytes that is related to intracellular cholesterol trafficking for the generation of high density lipoprotein in the brain.
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PMID:Apolipoprotein A-I induces translocation of protein kinase C[alpha] to a cytosolic lipid-protein particle in astrocytes. 1537 80

Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling, and atherogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular function and structure by blood flow. Although cyclosporin A (CsA), an inhibitory ligand of cyclophilin A, is a widely used immunosuppressive drug, it causes arterial hypertension in part by impairing eNOS-dependent vasodilation. Here we show that CsA inhibits fluid shear stress-mediated eNOS activation in endothelial cells via decreasing cholesterol content in caveolae. Exposure of cultured bovine aortic endothelial cells to 1 mum CsA for 1 h significantly inhibited NO production and eNOS phosphorylation at Ser-1179 induced by flow (shear stress=dynes/cm2). The effect of CsA was not related to inhibition of two known eNOS kinases, protein kinase B (Akt) and protein kinase A, because CsA did not affect Akt or protein kinase A activation. In rabbit aorta perfused ex vivo, CsA also significantly inhibited flow-induced eNOS phosphorylation at Ser-1179 but had no effect on Akt measured by phosphorylation at Ser-473. However, CsA treatment decreased cholesterol content in caveolae and displaced eNOS from caveolae, which may be caused by CsA disrupting the association of caveolin-1 and cyclophilin A. The magnitude of the cholesterol depleting effect was similar to that of beta-cyclodextrin, a cholesterol-binding molecule, and beta-cyclodextrin had a similar inhibitory effect on flow-mediated eNOS activation. Treating bovine aortic endothelial cells for 24 h with 30 mug/ml cholesterol blocked the CsA effect and restored eNOS phosphorylation in response to flow. These data suggest that decreasing cholesterol content in caveolae by CsA is a potentially important pathogenic mechanism for CsA-induced endothelial dysfunction and hypertension.
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PMID:Cyclosporin A inhibits flow-mediated activation of endothelial nitric-oxide synthase by altering cholesterol content in caveolae. 1538 26

Localization and coordinate phosphorylation/dephosphorylation of endothelial nitric oxide synthase (eNOS) are critical determinants for the basal and stimulated production of nitric oxide. Several phosphorylation sites in eNOS have been identified as targets of the cAMP-dependent protein kinase A (PKA). Basal eNOS activity is also regulated by interaction with caveolin-1, the major coat protein of caveolae. In the present study we have examined in rat aorta endothelium the subcellular steady-state distribution of eNOS, the catalytic subunit of PKA (PKA-c), and caveolin-1. Basal eNOS expression was found in two distinct locations, the endothelial cell surface and the Golgi complex. Cell surface eNOS was equally distributed over caveolar and non-caveolar membranes but was 2.5-fold enriched on luminal lamellipodia located at endothelial cell contacts. PKA-c colocalized with eNOS in the lamellipodia, whereas caveolin-1 was absent from these membrane domains. PKA-c was also found associated with cell surface caveolae and with tubulovesicular membranes of Golgi complex and endosomes. The topological proximity of eNOS with the catalytic subunit of PKA in restricted intracellular locations may provide mechanisms for differential PKA-mediated eNOS regulation.
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PMID:Colocalization of eNOS and the catalytic subunit of PKA in endothelial cell junctions: a clue for regulated NO production. 1538 74

The proliferation of smooth muscle cells (SMC) is a key event in the development of atherosclerosis. In addition to growth factors or cytokines, we have shown previously that n-3 polyunsaturated fatty acids (PUFAs) act in opposition to n-6 PUFAs by modulating various steps of the inflammatory process. We have investigated the molecular mechanisms by which the incorporation of the n-6 PUFA, arachidonic acid, increases the proliferation of rat SMC treated with interleukin-1beta, while the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), elicit no mitogenic response. Incorporation of EPA or DHA into SMC, which are then activated by interleukin-1beta to mimic inflammation, decreases promoter activity of the cyclin D1 gene and phosphorylation of the retinoblastoma protein. Together, our data demonstrate that n-3 effects are dependent on the Ras/Raf-1/extracellular signal regulated kinase (ERK)/mitogen-activated protein kinase pathway, and that down-regulation of the cyclin D1 promoter activity is mediated by the specific binding of the early growth response factor-1. Finally, we have shown that the incorporation of EPA and DHA also increased the concentration of caveolin-1 and caveolin-3 in caveolae, which correlated with n-3 PUFA inhibition of SMC proliferation through the mitogen-activated protein kinase pathway. We provide evidence indicating that, in contrast to n-6 PUFAs, n-3 PUFAs exert antiproliferative effects on SMC through the mitogen-activated protein kinase/ERK pathway.
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PMID:Modulation of cyclin D1 and early growth response factor-1 gene expression in interleukin-1beta-treated rat smooth muscle cells by n-6 and n-3 polyunsaturated fatty acids. 1556 Jul 87

3-Phosphoinositide-dependent protein kinase 1 (PDK1), a member of the serine/threonine kinase family, has been demonstrated to be crucial for cellular survival, differentiation, and metabolism. Here, we present evidence that PDK1 is associated with caveolin-1, a 22-kDa integral membrane protein, which is the principal structural and regulatory component of the caveolae membranes in COS-1. First, we noted the presence of two potential caveolin-1 binding motifs ((141)FFVKLYFTF(149) and (299)YDFPEKFF(306)) in the PDK1 catalytic domain. Using a pull-down approach, we observed that PDK1 interacts physically with caveolin-1 both in vivo and in vitro. Second, we detected the co-localization of PDK1 and caveolin-1 via confocal microscopy. The localization of PDK1 to the plasma membrane was disrupted by caveolin binding. Third, in transient transfection assays, interaction with caveolin-1 induced a substantial reduction in the in vivo serine/threonine phosphorylation of PDK1, whereas the caveolin-1 binding site mutant ((141)FFVKLYFTF(149) and (299)YDFPEKFF(306) change to (141)AFVKLAFTA(149) and (299)ADAPEFLA(306)) did not. Furthermore, a caveolin-1 scaffolding peptide (amino acids 82-101) functionally suppressed the self-phosphorylation and kinase activities of purified recombinant PDK1 protein. Thus, our observations indicated that PDK1 binds to caveolin-1 through its caveolin-binding motifs, and also that the protein-protein interaction between PDK1 and caveolin-1 regulates PDK1 self-phosphorylation, kinase activity, and subcellular localization.
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PMID:The subcellular localization of 3-phosphoinositide-dependent protein kinase is controlled by caveolin-1 binding. 1556 63

Beta-adrenergic receptor (beta-AR)-mediated vasorelaxation declines with age in humans and animal models. This is not caused by changes in expression of beta-AR, G alpha s, adenylyl cyclase, or protein kinase A but is associated with decreased cAMP production. Expression and activity of G protein receptor kinase-2 (GRK-2), which phosphorylates and desensitizes the beta-AR, increases with age in rat aortic tissue. Caveolin scaffolds the beta-AR, GRK, and other proteins within "signaling pockets" and inhibits GRK activity when bound. We questioned the effect of age on caveolin-1 expression and interaction between caveolin-1 and GRK-2 in vascular smooth muscle (VSM) isolated from 2-, 6-, 12-, and 24-mo-old male Fischer 344 rat aorta. Western blot analysis found expression of caveolin-1 declined with age (6-, 12- and 24-mo-old rat aortas express 92, 50, and 42% of 2-mo-old rat aortas, respectively). Results from density-buoyancy analysis showed a lower percentage of GRK in caveolin-1-specific fractions with age (6-, 12- and 24-mo-old rat aortas express 95, 56, and 12% of 2-mo-old rat aortas, respectively). Coimmunoprecipitation confirmed this finding; density of GRK in caveolin-1 immunoprecipitates was 97, 30, and 21% of 2-mo-old aortas compared with 6-, 12- and 24-mo-old animals, respectively. Immunohistocytochemistry and confocal microscopy confirmed that GRK-2 and caveolin-1 colocalize in VSM. These results suggest that in nonoverexpressed, intact tissue, the decline in beta-AR-mediated vasorelaxation may be caused by both a reduction in caveolin-1 expression and a reduction in binding of GRK-2 by caveolin-1. This could lead to an increase in the fraction of free GRK-2, which could phosphorylate and desensitize the beta-AR.
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PMID:Decline in caveolin-1 expression and scaffolding of G protein receptor kinase-2 with age in Fischer 344 aortic vascular smooth muscle. 1562 85

Y1 adrenocortical cells respond to ACTH with a characteristic rounding-up that facilitates cAMP signaling, critical for transport of cholesterol to the mitochondria and increase in steroid secretion. We here demonstrate that caveolin-1 participates in coupling activation of protein kinase A (PKA) to the control of cell shape. ACTH/8-Br-cAMP induced reorganization of caveolin-1-positive structures in correlation with the cellular rounding-up. Concomitant with this change, there was an increase in the phosphorylation of caveolin-1 (Tyr-14) localized at focal adhesions (FA) with reorganization of FA to rounded, ringlike structures. Colocalization with phalloidin showed that phosphocaveolin is present at the edge of actin filaments and that after ACTH stimulation F-actin dots at the cell periphery become surrounded by phosphocaveolin-1. These observations along with electron microscopy studies revealed these structures as podosomes. Podosome assembly was dependent on both PKA and tyrosine kinase activities because their formation was impaired after treatment with specific inhibitors [myristoylated PKI (mPKI) or PP2, respectively] previous to ACTH/8-Br-cAMP stimulation. These results show for the first time that ACTH induces caveolin-1 phosphorylation and podosome assembly in Y1 cells and support the view that the morphological and functional responses to PKA activation in steroidogenic cells are related to cytoskeleton dynamics.
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PMID:ACTH-induced caveolin-1 tyrosine phosphorylation is related to podosome assembly in Y1 adrenal cells. 1574 89

Classically, nitric oxide (NO) formed by endothelial NO synthase (eNOS) freely diffuses from its generation site to smooth muscle cells where it activates soluble guanylyl cyclase (sGC), producing cGMP. Subsequently, cGMP activates both cGMP- and cAMP-dependent protein kinases [cGMP-dependent protein kinase (PKG) and cAMP-dependent protein kinase (PKA), respectively], leading to smooth muscle relaxation. In endothelial cells, eNOS has been localized to caveolae, small invaginations of the plasma membrane rich in cholesterol. Membrane cholesterol depletion impairs acetylcholine (ACh)-induced relaxation due to alteration in caveolar structure. Given the nature of NO to be more soluble in a hydrophobic environment than in water, and assuming that colocalization of components in a signal transduction cascade seems to be a critical determinant of signaling efficiency by eNOS activation, we hypothesize that sGC, PKA, and PKG activation may occur at the plasma membrane caveolae. In endothelium-intact rat aortic rings, the relaxation induced by ACh, by the sGC activator 3-(5'-hydroxymethyl-2'furyl)-1-benzyl indazole (YC-1), and by 8-bromo-cGMP was impaired in the presence of methyl-beta-cyclodextrin, a drug that disassembles caveolae by sequestering cholesterol from the membrane. sGC, PKG, and PKA were colocalized with caveolin-1 in aortic endothelium, and this colocalization was abolished by methyl-beta-cyclodextrin. Methyl-beta-cyclodextrin efficiently disassembled caveolae in endothelium. In summary, our results provide evidence of compartmentalization of sGC, PKG, and PKA in endothelial caveolae contributing to NO signaling cascade, giving new insights by which the endothelium mediates vascular smooth muscle relaxation.
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PMID:Dynamic association of nitric oxide downstream signaling molecules with endothelial caveolin-1 in rat aorta. 1577 64

Stimulation of endothelin receptors (ETRs) leads to activation of the extracellular signal-regulated protein kinase (ERK) cascade. It is unclear whether compartmentalization to lipid rafts is necessary for proper endothelin signaling, as methodologies employed to isolate and study caveolae involve detergent extraction, which may induce aggregation of membrane-associated proteins. The present study was to determine if components of the endothelin-1 (ET-1) pathway leading to ERK activation localize to caveolae and constitute preformed signalosomes. Microsomes were prepared from intact ventricular myocardium, in the absence of detergents, and fractionated by differential and sucrose-density gradient centrifugation to determine if caveolins and components of the ETRs post-receptor signaling cascade were in vesicles having similar physical properties. Confocal fluorescence microscopy, followed by digital deconvolution, was employed to determine if the signaling proteins colocalized with caveolin within intact, freshly isolated adult myocytes. With the exception of ET(A)Rs, proteins from the ET-1 pathway copurified in part or entirely (Galpha(11)), with caveolin-1 and caveolin-3. In contrast, with the exception of Galpha(q/11), Galpha(i3) and Gbeta G-protein subunits, most of the proteins studied showed little colocalization with caveolin-3. Thus, although components of the ET-1 signaling pathway may exist in vesicles having similar characteristics to vesicles containing caveolin, these proteins did not associate with caveolae in intact myocytes. The lack of detectable colocalization of caveolin-3 with proteins within the endothelin post-receptor signaling system in intact myocytes argues against the presence of a preformed, caveolae-associated signalosome.
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PMID:Sub-cellular distribution of endothelin signaling pathway components in ventricular myocytes and heart: lack of preformed caveolar signalosomes. 1580 43

During vascular injury, the proliferation and migration of smooth muscle cells leads to characteristic neointima formation, which can be exacerbated by genetic depletion of caveolin-1 or heme oxygenase 1 (HO-1), and inhibited by carbon monoxide (CO), a by-product of heme oxygenase 1 activity. CO inhibited smooth muscle cell proliferation by activating p38 mitogen-activated protein kinase (MAPK) and p21(Waf1/Cip1). Exposure to CO increased caveolin-1 expression in neointimal lesions of injured aorta and in vitro by activating guanylyl cyclase and p38 MAPK. p38beta-/- fibroblasts did not induce caveolin-1 in response to CO, and exhibited a diminished basal caveolin-1 expression, which was restored by p38beta gene transfer. p38beta MAPK down-regulated extracellular signal-regulated protein kinase 1/2 (ERK-1/2), which can repress caveolin-1 transcription. Genetic depletion of caveolin-1 abolished the antiproliferative effect of CO. Thus, we demonstrate that CO, by activating p38beta MAPK, up-regulates caveolin-1, which acts as a tumor suppressor protein that mediates the growth inhibitory properties of this gas.
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PMID:Caveolin-1 expression by means of p38beta mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide. 1605 4


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