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

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When PI3Ks are deregulated by aberrant surface receptors or modulators, accumulation of PtdIns(3,4,5)P3 leads to increased cell growth, proliferation and contact-independent survival. The PI3K/PKB/TOR axis controls protein synthesis and growth, while PtdIns(3,4,5)P3-mediated activation of Rho GTPases directs cell motility. PI3K activity has been linked to the formation of tumors, metastasis, chronic inflammation, allergy and cardiovascular disease. Although increased PtdIns(3,4,5)P3 is a well-established cause of disease, it is seldom known which PI3K isoform is implied. Recent work has demonstrated that PI3Kgamma contributes to the control of cAMP levels in the cardiac system, where the protein acts as a scaffold, but not as a lipid kinase.
...
PMID:Phosphoinositide 3-kinase in disease: timing, location, and scaffolding. 1578 May 90

An elevated circulating level of the adipocyte-derived satiety hormone leptin is an independent risk factor for cardiovascular disease. Because thrombus formation is a major cause of acute coronary events and leptin was shown previously to facilitate ADP-induced platelet aggregation, we chose to define the signaling events involved in leptin-mediated platelet activation. Using pharmacological, biochemical, and cell biological approaches, we show that leptin-induced platelet activation required activation of a signaling cascade that included the long form of the leptin receptor, three kinases [Janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (PKB/Akt)], the insulin receptor substrate-1 (IRS-1), and the major human platelet cAMP phosphodiesterase phosphodiesterase 3A (PDE3A). Moreover, we identify a role for an intraplatelet LEPR/JAK2/IRS-1/PI3K/PKB/PDE3A molecular complex that allows for the selective leptin-mediated activation of platelets. Our data demonstrate that leptin promotes platelet activation, provides a mechanistic basis for the prothrombotic effect of this hormone, and identifies a potentially novel therapeutic avenue to limit obesity-associated cardiovascular disease.
...
PMID:Leptin-mediated activation of human platelets: involvement of a leptin receptor and phosphodiesterase 3A-containing cellular signaling complex. 1588 25

Adrenomedullin (AM) is a potent, long-lasting vasodilator peptide that was originally isolated from human pheochromocytoma. AM signaling is of particular significance in endothelial cell biology since the peptide protects cells from apoptosis, promotes angiogenesis, and affects vascular tone and permeability. The angiogenic effect of AM is mediated by activation of Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2, and focal adhesion kinase in endothelial cells. Both AM and its receptor, calcitonin receptor-like receptor, are upregulated through a hypoxia-inducible factor-1-dependent pathway under hypoxic conditions. Thus AM signaling plays an important role in the regulation of angiogenesis in hypoxic conditions. Recently, we have developed a nonviral vector, gelatin. Positively charged gelatin holds negatively charged plasmid DNA in its lattice structure. DNA-gelatin complexes can delay gene degradation, leading to efficient gene transfer. Administration of AM DNA-gelatin complexes induces potent angiogenic effects in a rabbit model of hindlimb ischemia. Thus gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of tissue ischemia. Endothelial progenitor cells (EPCs) play an important role in endothelial regeneration. Interestingly, EPCs phagocytose ionically linked DNA-gelatin complexes in coculture, which allows nonviral gene transfer into EPCs. AM gene transfer into EPCs inhibits cell apoptosis and induces proliferation and migration, suggesting that AM gene transfer strengthens the therapeutic potential of EPCs. Intravenous administration of AM gene-modified EPCs regenerate pulmonary endothelium, resulting in improvement of pulmonary hypertension. These results suggest that in vivo and in vitro transfer of AM gene using gelatin may be applicable for intractable cardiovascular disease.
...
PMID:Adrenomedullin: angiogenesis and gene therapy. 1588 52

Aldosterone is currently recognized as a risk hormone for cardiovascular disease. However, the cellular mechanism by which aldosterone acts on vasculature has not been well understood. In the present study, we investigated whether aldosterone affects angiotensin-converting enzyme (ACE) gene expression in rat endothelial cells. Cultured rat aortic endothelial cells (RAECs) from Sprague-Dawley rats were used in the study. ACE mRNA levels and its enzyme activities in RAECs were examined by real-time RT-PCR and enzyme assay using hippuryl-His-Leu as substrates, respectively. Aldosterone significantly increased steady-state ACE mRNA levels and its enzymatic activities. This effect was dose dependent and time dependent and abolished by mineralocorticoid receptor antagonist spironolactone or transcription inhibitor actinomycin D. Dexamethasone also increased steady-state ACE mRNA levels, whose effect was completely blocked by glucocorticoid receptor antagonist RU486, but not by spironolactone. By contrast, the aldosterone-induced ACE mRNA expression was only partially blocked by RU486. The stimulatory effect of aldosterone on ACE mRNA expression was completely blocked by a protein tyrosine kinase inhibitor (genistein) and JAK2 inhibitor (AG490), partially by Src kinase inhibitor (PP2) and epidermal growth factor receptor kinase inhibitor (AG1478), but not by platelet-derived growth factor receptor kinase inhibitor (AG1296). Transfection of dominant-negative JAK2 construct, but not wild-type construct, significantly blocked the aldosterone-induced ACE mRNA up-regulation. Furthermore, aldosterone induced phosphorylation of JAK2, whose effect was blocked by spironolactone and actinomycin D. In conclusion, the present study demonstrates for the first time that aldosterone induces ACE gene expression and its enzyme activity mainly via a mineralocorticoid receptor-mediated and JAK2-dependent pathway in rat endothelial cells. This may constitute a positive feedback loop for a local renin-angiotensin system, possibly involved in the development of aldosterone-induced endothelial dysfunction and vascular injury.
...
PMID:Aldosterone induces angiotensin converting enzyme gene expression via a JAK2-dependent pathway in rat endothelial cells. 1593 31

A lack of exercise training and/or regular physical activity is a known risk factor for cardiovascular disease. Exercise training induces marked vascular remodeling by increasing angiogenesis and arteriogenesis. These changes in the architecture of the vascular tree are likely associated with functional changes and improved organ blood flow. Physical forces such as shear stress, transmural pressure and cyclic stretch activate mechanotransduction mechanisms in endothelial and smooth muscle cells that are mediated by integrins and associated RhoA small GTPase. They stimulate various signal transduction pathways involving phosphorylation of kinases such as focal adhesion kinase, c-Src, Akt kinase, phosphatidylinositol 3-kinase, myosin light chain kinase and mitogen-activated protein kinases (MAPK) such as extracellular signal-regulated kinase (ERK). These mechanisms result in upregulation of genes mediating antiatherogenic effects by promoting antiapoptotic and antiproliferative signals, by increasing vascular NO bioavailability and by changing calcium handling and the vascular myogenic response to pressure. Exercise-induced increase of vascular eNOS expression and of eNOS Ser-1177 phosphorylation is most likely an important and potentially vasoprotective effect of exercise training. The underlying mechanisms involve cell membrane proteins such as integrins and products of vascular oxidative stress such as hydrogen peroxide. Exercise-induced eNOS expression is transient and reversible and regulated by factors such as angiogenesis, arteriogenesis and antioxidative effects including upregulation of superoxide dismutases (SOD1, SOD3) and downregulation of NAD(P)H oxidase, which likely blunts the effects of oxidative stress. Based on these observations, it appears reasonable to assume that exercise training can be viewed as an effective antioxidant and antiatherogenic therapy.
...
PMID:Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy? 1593 34

Naturally occurring single nucleotide polymorphisms have been identified in human CX3CR1, the chemokine receptor for fractalkine (FKN/CX3CL1). Individuals carrying the I249/M280 variant of CX3CR1 have a lower risk of cardiovascular disease compared with those homozygous for the common variant (V249/T280). The precise molecular basis for this phenotype is unclear, although differences in FKN binding, adhesive properties, and signaling efficiency between the CX3CR1 variants have been reported. FKN binding to CX3CR1 leads to an increase in intracellular calcium, actin rearrangement, and activation of the mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K) pathways. Regulation of these signaling pathways underlies the known roles for FKN in cell survival, proliferation, and migration. In the present study, we demonstrate that FKN stimulates phosphorylation of protein kinase B (Akt/PKB) in Chinese hamster ovary cells individually expressing the naturally occurring variants of human CX3CR1-, as well as rat CX3CR1-, but not in murine CX3CR1-expressing cells. Substitution of Pro326 in the C terminus of murine CX3CR1 with Ser (residue found in the analogous position of human CX3CR1) produced a mutant receptor that mimicked the human receptor in its ability to stimulate the phosphorylation of both Akt and extracellular signal-regulated kinase in a time-, PI3K-, and pertussis toxin-sensitive G-protein-dependent manner. These results identify a critical structural determinant of CX3CR1 important for activation of downstream signaling pathways.
...
PMID:Proline 326 in the C terminus of murine CX3CR1 prevents G-protein and phosphatidylinositol 3-kinase-dependent stimulation of Akt and extracellular signal-regulated kinase in Chinese hamster ovary cells. 1616 68

Pathway specific resistance to insulin signaling through PI 3-kinase/Akt/eNOS associated with a normal or hyper-activated MAP kinase signaling in vascular tissues has recently been proposed as a candidate link between cardiovascular disease and insulin resistance. Growth stimulatory pathways other than ERK/MAP kinase, such as JAK/STAT have not yet been investigated in vessels of animal models of insulin resistance. Here we have examined whether insulin is able to activate JAK2/STAT pathway in rat aorta and also the regulation of this pathway in an animal model of obesity/insulin resistance. Our results demonstrate that insulin activates JAK2 tyrosine kinase activity in rat aorta in parallel with the activation of STAT3 and STAT5a/b. Moreover, it is shown that, in obese animals, JAK2/STAT and MAP kinase pathways are hyper-activated in response to insulin, which occurs in association with a reduced activation of PI 3-kinase/Akt pathway in aorta. The results of the present study suggest that, besides ERK/MAP kinase pathway, another potentially pro-atherogenic pathway, JAK2/STAT is hyper-activated in vessels in a state of insulin resistance and this phenomenon, in association with the inhibition of the PI 3-kinase/Akt pathway, may play an important role in the pathogenesis of cardiovascular diseases.
...
PMID:Effect of obesity on insulin signaling through JAK2 in rat aorta. 1623 56

They were more than just another kinases (JAK), when they were first described in the late 80s and named JAK kinases. The mandatory role of this novel family of dual active janus kinases (JAK) and their substrates the signal transducers and activators of transcription (STAT) was demonstrated in mice who died during embryogenesis when lacking a functional allele, e.g. that of JAK2. Initially, the JAK/STAT signaling pathway was discovered as the primary mediator of intracellular signaling induced by interferon in hematopoietic and immune cells. Nowadays, it is well accepted that JAK kinases and STAT proteins are constitutively expressed in the vessel wall in a cell type specific manner and transfer intracellular signaling events of various receptor families, e.g. that of cytokines, growth factors and vasoactive peptides such as angiotensin II (Ang II) or endothelin. The potential impact of the JAK/STAT signaling pathway on cardiovascular pathophysiology and disease development arise from reports describing that JAKs may bind directly to the angiotensin II type I (AT(1)) receptor, thereby enhancing their phosphorylation in various cell types of the vessel wall. More interestingly, these signaling events are modulated by NAD(P)H oxidase-derived superoxide anions which directly phosphorylate JAK2 and thereby control JAK2 activity. A potential impact was also described for atherosclerotic plaque development in which the activation of JAKs and STATs seems to be critical. Based on these observations, we here review the role of the JAK/STAT signaling pathways as critical regulator for cardiovascular disease development, i.e. atherosclerotic plaque progression or the manifestation of arterial hypertension.
...
PMID:JANUS under stress--role of JAK/STAT signaling pathway in vascular diseases. 1627 17

Cardiovascular disease is the main cause of death and disability in the Western society. Lipoproteins play an important role in the development of this disease and affect different cell types involved in atherosclerosis and thrombosis. Based on their density, five classes of lipoproteins have been identified which all influence cells via distinct mechanisms. Modification turns lipoproteins into atherogenic particles with a prominent role in atherogenesis. The interaction of lipoproteins with platelets has been under investigation for a number of years. Especially the role of LDL in platelet signaling has been studied intensively as platelets of hypercholesterolemic patients are hyperreactive and show hyperaggregability in vitro and enhanced activity in vivo, suggesting that LDL enhances platelet responsiveness. Several signaling pathways induced by LDL have been revealed in vitro, such as signaling via p38 mitogen-activated protein kinase (p38MAPK) and p125 focal adhesion kinase (p125FAK). HDL opposes the activating properties of LDL on platelets, whereas the effects of chylomicrons, VLDL or IDL on platelet function are controversial. Modification of lipoproteins is associated with the generation of new constituents with new signaling properties. In particular, the platelet-activating properties of lysophosphatidic acid, which is a constituent of atherosclerotic plaques and is generated upon oxidation of LDL, have been investigated intensively. This review provides a summary of the activation of signaling pathways after platelet-lipoprotein interactions, with special emphasis on the role of these interactions in the development of thrombosis and atherosclerosis.
...
PMID:Platelet signaling induced by lipoproteins. 1661 Oct 46

Cardiovascular disease is the main cause of death and disability in the Western society. Lipoproteins are important in the development of cardiovascular disease since they change the properties of different cells involved in atherosclerosis and thrombosis. The interaction of platelets with lipoproteins has been under intense investigation. Particularly the initiation of platelet signaling pathways by low density lipoprotein (LDL) has been studied thoroughly, since platelets of hypercholesterolemic patients, whose plasma contains elevated LDL levels due to absent or defective LDL receptors, show hyperaggregability in vitro and enhanced activity in vivo. These observations suggest that LDL enhances platelet responsiveness. Several signaling pathways induced by LDL have been revealed in vitro, such as signaling via p38 mitogen-activated protein kinase and p125 focal adhesion kinase. High density lipoprotein (HDL) consists of two subtypes, HDL(2) and HDL(3), which have opposing effects on platelet activation. This review provides a summary of the activation of signaling pathways after platelet-LDL and platelet-HDL interaction, with special emphasis on their role in the development of thrombosis and atherosclerosis.
...
PMID:Platelet activation by low density lipoprotein and high density lipoprotein. 1687 76


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---