Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we report that staurosporine, a known PKC inhibitor, enhanced in vitro angiogenesis. Endothelial cells plated in a three-dimensional matrix formed cords and enclosed structures within 4-6 hours. The cells in cord structures became elongated during the subsequent incubation. Tube formation was confirmed by confocal microscopy. Addition of VEGF enhanced the early responses of endothelial cells, leading to enhanced formation of cords. Staurosporine unexpectedly also enhanced the early endothelial responses, leading to faster alignment of cells and assembly into tube-like structures. At concentrations inhibitory to endothelial cell PKC activity, staurosporine produced 91% and 203% increases in the number of cords and the enclosed structures, respectively, as compared to the controls. Other selective inhibitors of PKC did not stimulate in vitro angiogenesis in the absence or presence of VEGF. Further investigation showed that inhibition of PI-3 kinase and Raf-1 significantly reduced the effects of staurosporine. Staurosporine-induced in vitro angiogenesis required integrins alpha2 and alphavbeta3 and was associated with significantly enhanced FAK phosphorylation. These data indicate that staurosporine enhances in vitro angiogenesis by a means unrelated to its PKC inhibition. The data suggest that enhancement of in vitro angiogenesis by staurosporine involves integrin-mediated signaling, including the stimulation of FAK phosphorylation.
J Cardiovasc Pharmacol 2005 Jan
PMID:Staurosporine promotes endothelial cell assembly and FAK phosphorylation during in vitro angiogenesis. 1561 75

Expression of endothelin-B receptor gradually increases as melanocytic lesions progress to melanoma, suggesting that endothelin-B receptor and its ligands, endothelin-1 and endothelin- 3, play a role in the melanoma progression. The selective blockade of endothelin-B receptor results in inhibition of focal adhesion kinase and mitogen-activated protein kinase phosphorylation and cell proliferation induced by endothelins in human melanoma cell lines. In these cells, endothelins induce downregulation of E-cadherin expression and concomitant upregulation of transcriptional factor Snail. Activation of the endothelin-B receptor pathway by endothelins also upregulates N-cadherin, phosphorylates the gap junctional protein connexin 43, increases alphavbeta3 and alpha2beta1 integrin expression and tumor proteolytic activity, thus enhancing endothelin-B receptor-mediated cell adhesion, migration and invasiveness. In this study we demonstrated that activation of the endothelin-B receptor pathway by endothelin-1 and endothelin-3 contributes to disruption of normal host-tumor interactions by downregulating, at mRNA and protein levels, the expression of E-cadherin and associated alpha-catenin and beta-catenin adhesion proteins, which are critical for E-cadherin function. A-192621, an orally active non-peptide endothelin-B receptor antagonist, significantly inhibited melanoma growth in nude mice, suggesting that the pharmacological interruption of endothelin-B receptor signaling by endothelin-B receptor antagonist may represent a new therapeutic approach in the treatment of cutaneous melanoma.
J Cardiovasc Pharmacol 2004 Nov
PMID:Endothelin-B receptor blockade inhibits molecular effectors of melanoma cell progression. 1583 63

The signaling pathways of endothelin-1-induced contraction, including the role of protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), protein kinase C (PKC) and RhoA/Rho-kinase were studied using rabbit basilar arteries by isometric tension and Western blot. The following results were observed: (1) endothelin-1 produced phosphorylation of MAPK and RhoA and contraction by activation of endothelin-A but not endothelin-B receptors; (2) MAPK inhibitors, PD 98059 and U0126, PTK inhibitor, genistein, Src kinase inhibitor, damnacanthal, and Janus tyrosine kinase (JAK2) inhibitor, AG-490, abolished endothelin-1-induced contraction and MAPK immunoreactivity; (3) PTK inhibitor, staurosporine, and phosphatidylinositol 3-kinase (PI- 3K) inhibitor wortmannin abolished endothelin-1 induced contraction but not MAPK immunoreactivity; (4) Rho-kinase inhibitor, Y-27632, reduced endothelin-1-induced contraction; (5) PI-3K inhibitor, wortmannin, but not PKC and PTK inhibitors, reduced endothelin-1-induced RhoA activation; (6) endothelin-1 increased the level of myosin light chain (MLC) phosphorylation, and Rho-kinase inhibitor, Y-27632, reduced the effect of endothelin- 1 on MLC phosphorylation. This study demonstrated that three signaling pathways Src-JAK2-PTK-MAPK, PI-3K-RhoA-Rhokinase- MLC and PKC all contribute to endothelin-1-induced contraction in the rabbit basilar artery. MAPK is downstream of PTK, Src and JAK pathways. PI-3 kinase and MLC might be the upstream and downstream factors of RhoA activation.
J Cardiovasc Pharmacol 2004 Nov
PMID:Signal transduction of ET-1 in contraction of cerebral arteries. 1583 90

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.
Cardiovasc Res 2005 Aug 01
PMID:Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy? 1593 34

The mechanical stress imposed by hemodynamic overload on heart walls is a primary event in triggering the cardiac hypertrophic response. Integrins, a class of membrane receptors, are major players in transmitting the mechanical force across the plasma membrane and sensing the mechanical load in cardiomyocytes. In fact, integrins, together with a number of associated cytoskeletal proteins, connect the sarcomeric contractile apparatus to the extracellular matrix across the plasma membrane and trigger intracellular signaling pathways activating the cardiomyocyte hypertrophy program. In this review, we will discuss the role of the muscle-specific integrin isoform beta1D and of associated proteins such as FAK, melusin, vinculin, zyxin, VASP, and migfilin that are the most upstream elements ("initiators") activated by mechanical strain. These molecules trigger a coordinated downstream signaling cascade involving proteins such as AKT, RAS, and MAPKs that execute the biochemical program leading to cardiomyocyte hypertrophy. Better understanding of the functional role of the initiator elements is of key importance to developing novel strategies to control cardiac hypertrophy and prevent heart failure.
Cardiovasc Res 2006 Jun 01
PMID:Integrin signalling: the tug-of-war in heart hypertrophy. 1646 4

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.
Cardiovasc Hematol Agents Med Chem 2006 Apr
PMID:Platelet signaling induced by lipoproteins. 1661 Oct 46

The molecular pathogenesis of the myeloproliferative disorders (MPD) is poorly understood, except for chronic myeloid leukemia (CML). Recently, several groups have discovered a novel recurrent unique acquired clonal mutation in a tyrosine-kinase JAK2 in patients with Philadelphia-negative MPD and other myeloid disorders. It consists in a guanine-to-thymine change encoding a valine to phenylalanine at codon 617 (JAK2 V617F). JAK2 and the other members of the Janus kinase family are tyrosine kinases that function as intermediates between membrane receptors and intracellular signalling molecules. The mutation occurs within the enzymatically inactive JH2 pseudo-kinase domain that regulates the active JH1 kinase domain. The JAK2 activation leads to constitutive JAK and STAT (activators of transcription) hyperactivation with induction of growth factor hypersensitivity and cell transformation. Some authors have found a higher risk of vascular thrombosis and higher platelet activation when the mutation is present. Therefore, the JAK2 mutation offers a molecular target for new drugs investigation in a similar way to bcr/abl rearrangement in CML. For all these reasons, several studies related to JAK2 have arisen in the last year. In this report, we will review the literature and discuss its possible clinical and prognostic significance.
Cardiovasc Hematol Agents Med Chem 2007 Jul
PMID:JAK2 as a molecular marker in myeloproliferative diseases. 1763 Sep 45

Activation of the transcription factor signal transducers and activators of transcription (STAT) 3 is a defining feature of the interleukin (IL)-6 family of cytokines, which include IL-6, leukemia inhibitory factor, and cardiotrophin-1. These cytokines, as well as STAT3 activation, have been shown to be protective for cardiac myocytes and necessary for ischemia preconditioning. However, the mechanisms that regulate IL-6-type cytokine signaling in cardiac myocytes are largely unexplored. We propose that the protective character of IL-6-type cytokine signaling in cardiac myocytes is determined principally by three mechanisms: redox status of the nonreceptor tyrosine kinase Janus kinase 1 (JAK) 1 that activates STAT3, phosphorylation of STAT3 within the transcriptional activation domain on serine 727, and STAT3-mediated induction of suppressor of cytokine signaling (SOCS) 3 that terminates IL-6-type cytokine signaling. Moreover, we hypothesize that hyperactivation of the JAK kinases, particularly JAK2, mismatched STAT3 serine-tyrosine phosphorylation or heightened STAT3 transcriptional activity, and SOCS3 induction may ultimately prove detrimental. Here we summarize recent evidence that supports this hypothesis, as well as additional possible mechanisms of JAK-STAT regulation. Understanding how IL-6-type cytokine signaling is regulated in cardiac myocytes has great significance for exploiting the therapeutic potential of these cytokines and the phenomenon of preconditioning.
J Cardiovasc Pharmacol 2007 Aug
PMID:Can the protective actions of JAK-STAT in the heart be exploited therapeutically? Parsing the regulation of interleukin-6-type cytokine signaling. 1770 29

Vascular smooth muscle tone plays a fundamental role in regulating blood pressure, blood flow, microcirculation, and other cardiovascular functions. The cellular and molecular mechanisms by which vascular smooth muscle contractility is regulated are not completely elucidated. Recent studies show that the actin cytoskeleton in smooth muscle is dynamic, which regulates force development. In this review, evidence for actin polymerization in smooth muscle upon external stimulation is summarized. Protein kinases such as Abelson tyrosine kinase, focal adhesion kinase, Src, and mitogen-activated protein kinase have been documented to coordinate actin polymerization in smooth muscle. Transmembrane integrins have also been reported to link to signaling pathways modulating actin dynamics. The roles of Rho family of the small proteins that bind to guanosine triphosphate (GTP), also known as GTPases, and the actin-regulatory proteins, including Crk-associated substrate, neuronal Wiskott-Aldrich Syndrome protein, the Arp2/3 complex, and profilin, and heat shock proteins in regulating actin assembly are discussed. These new findings promote our understanding on how smooth muscle contraction is regulated at cellular and molecular levels.
J Cardiovasc Pharmacol Ther 2008 Jun
PMID:Physiologic properties and regulation of the actin cytoskeleton in vascular smooth muscle. 1821 60

Currently available drug-eluting stents have been shown to reduce the prevalence of in-stent restenosis. However, their use is limited by their enormous cost and unwanted side effects associated with both drugs, sirolimus and paclitaxel, presently used to coat most of the stents clinically available. Due to their lack of selectivity with respect to targeted cell types these drugs do not only inhibit vascular smooth muscle cell proliferation underlying neointima formation, they also compromise endothelial repair increasing the risk for subacute thrombosis following implantation of drug-eluting stents. Accordingly, there is need for new cost-effective agents capable to inhibit restenosis without clinically relevant, unwanted side effects. In the present paper a selection of the most important patent applications published within the last 3 years and claiming the use of homologous cellular and extracellular agents as therapeutics or targets to prevent restenosis are reviewed. Such agents include c-Jun, the focal adhesion kinase (FAK) and its inhibitor FAK-related non-kinase (FRNK), estrogen receptors, variants of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) as well as some so far poorly characterized factors supposedly involved in the control of cell proliferation, inflammation and apoptosis. Such agents promise to be cost-effective and, in some cases, potentially devoid of unwanted side effects. Clinical long-term studies have yet to support such notions.
Recent Pat Cardiovasc Drug Discov 2006 Jan
PMID:Recently patented applications of homologous cellular and extracellular agents as therapeutics or targets for the prevention of restenosis post-angioplasty. 1822 Oct 74


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