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Regulation of arterial reactivity by concurrent signaling through the E-prostanoid receptor 3 and angiotensin receptor 1.
Kraemer MP, Choi H, Reese J, Lamb FS, Breyer RM
(2016) Vascul Pharmacol 84: 47-54
MeSH Terms: Angiotensin II, Animals, Calcium, Dinoprostone, Dose-Response Relationship, Drug, Femoral Artery, Focal Adhesion Kinase 2, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor, Angiotensin, Type 1, Receptors, Prostaglandin E, EP3 Subtype, Vasoconstriction, rho-Associated Kinases
Show Abstract · Added April 6, 2017
Prostaglandin E2 (PGE2), a cyclooxygenase metabolite that generally acts as a systemic vasodepressor, has been shown to have vasopressor effects under certain physiologic conditions. Previous studies have demonstrated that PGE2 receptor signaling modulates angiotensin II (Ang II)-induced hypertension, but the interaction of these two systems in the regulation of vascular reactivity is incompletely characterized. We hypothesized that Ang II, a principal effector of the renin-angiotensin-aldosterone system, potentiates PGE2-mediated vasoconstriction. Here we demonstrate that pre-treatment of arterial rings with 1nM Ang II potentiated PGE2-evoked constriction in a concentration dependent manner (AUC-Ang II 2.778±2.091, AUC+Ang II 22.830±8.560, ***P<0.001). Using genetic deletion models and pharmacological antagonists, we demonstrate that this potentiation effect is mediated via concurrent signaling between the angiotensin II receptor 1 (AT1) and the PGE2 E-prostanoid receptor 3 (EP3) in the mouse femoral artery. EP3 receptor-mediated vasoconstriction is shown to be dependent on extracellular calcium in combination with proline-rich tyrosine kinase 2 (Pyk2) and Rho-kinase. Thus, our findings reveal a novel mechanism through which Ang II and PGE2 regulate peripheral vascular reactivity.
Copyright © 2016 Elsevier Inc. All rights reserved.
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15 MeSH Terms
RGD-dependent binding of TP508 to integrin alphavbeta3 mediates cell adhesion and induction of nitric oxide.
Derkach DN, Wadekar SA, Perkins KB, Rousseau E, Dreiza CM, Cheung-Flynn J, Ramos HC, Ugarova TP, Sheller MR
(2010) Thromb Haemost 104: 172-82
MeSH Terms: Animals, Antibodies, Blocking, Aorta, Carbachol, Cell Adhesion, Cell Line, Endothelial Cells, Focal Adhesion Kinase 2, Humans, Integrin alphaVbeta3, Male, Mitogen-Activated Protein Kinase 3, Nitric Oxide, Oligopeptides, Peptide Fragments, Protein Binding, Rats, Rats, Sprague-Dawley, Thrombin, Vasodilation
Show Abstract · Added March 9, 2015
TP508, a 23-amino acid RGD-containing synthetic peptide representing residues 508 to 530 of human prothrombin, mitigates the effects of endothelial dysfunction in ischaemic reperfusion injury. The objective of this study was to investigate whether TP508 binds to members of the integrin family of transmembrane receptors leading to nitric oxide synthesis. Immobilised TP508 supported adhesion of endothelial cells and alphavbeta3-expressing human embryonic kidney cells in a dose- and RGD-dependent manner. Soluble TP508 also inhibited cell adhesion to immobilised fibrinogen. The involvement of alphavbeta3 was verified with function-blocking antibodies and surface plasmon resonance studies. Adhesion of the cells to immobilised TP508 resulted in an induction of phosphorylated FAK and ERK1/2. In endothelial cells, TP508 treatment resulted in an induction of nitric oxide that could be inhibited by LM609, an alphavbeta3-specific, function-blocking monoclonal antibody. Finally, TP508 treatment of isolated rat aorta segments enhanced carbachol-induced vasorelaxation. These results suggest that TP508 elicits a potentially therapeutic effect through an RGD-dependent interaction with integrin alphavbeta3.
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20 MeSH Terms
The role of proline-rich protein tyrosine kinase 2 in differentiation-dependent signaling in human epidermal keratinocytes.
Schindler EM, Baumgartner M, Gribben EM, Li L, Efimova T
(2007) J Invest Dermatol 127: 1094-106
MeSH Terms: Calcium, Cell Differentiation, Cell Nucleus, Cells, Cultured, Epidermal Cells, Epidermis, Focal Adhesion Kinase 2, Gene Expression Regulation, Humans, Indoles, Keratinocytes, Maleimides, Protein Kinase C, Protein Precursors, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Signal Transduction, Tetradecanoylphorbol Acetate
Show Abstract · Added May 30, 2013
Non-receptor tyrosine kinase proline-rich protein tyrosine kinase 2 (Pyk2) functions as an integrator of multiple signaling pathways involved in the regulation of fundamental cellular processes. Pyk2 expression, regulation, and functions in skin have not been examined. Here we investigated the expression and subcellular localization of Pyk2 in human epidermis and in primary human keratinocytes, and studied the mechanisms of Pyk2 activation by differentiation-inducing stimuli, and the role of Pyk2 as a regulator of keratinocyte differentiation. We demonstrate that Pyk2 is abundantly expressed in skin keratinocytes. Notably, the endogenous Pyk2 protein is predominantly localized in keratinocyte nuclei throughout all layers of healthy human epidermis, and in cultured human keratinocytes. Pyk2 is activated by treatment with keratinocyte-differentiating agents, 12-O-tetradecanoylphorbol-13-acetate and calcium via a mechanism that requires intracellular calcium release and functional protein kinase C (PKC) and Src activities. Particularly, differentiation-promoting PKC delta and PKC eta elicit Pyk2 activation. Our data show that Pyk2 increases promoter activity and endogenous protein levels of involucrin, a marker of keratinocyte terminal differentiation. This regulation is associated with increased expression of Fra-1 and JunD, activator protein-1 transcription factors known to be required for involucrin expression. Altogether, these results provide insights into Pyk2 signaling in epidermis and reveal a novel role for Pyk2 in regulation of keratinocyte differentiation.
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18 MeSH Terms
Inhibition of Pkhd1 impairs tubulomorphogenesis of cultured IMCD cells.
Mai W, Chen D, Ding T, Kim I, Park S, Cho SY, Chu JS, Liang D, Wang N, Wu D, Li S, Zhao P, Zent R, Wu G
(2005) Mol Biol Cell 16: 4398-409
MeSH Terms: Animals, Apoptosis, Cell Adhesion, Cell Communication, Cell Differentiation, Cell Line, Cell Movement, Cilia, Dogs, Extracellular Signal-Regulated MAP Kinases, Focal Adhesion Kinase 2, Integrins, Kidney Tubules, Collecting, Mice, Polycystic Kidney, Autosomal Recessive, RNA Interference, Receptors, Cell Surface, Signal Transduction
Show Abstract · Added December 10, 2013
Fibrocystin/polyductin (FPC), the gene product of PKHD1, is responsible for autosomal recessive polycystic kidney disease (ARPKD). This disease is characterized by symmetrically large kidneys with ectasia of collecting ducts. In the kidney, FPC predominantly localizes to the apical domain of tubule cells, where it associates with the basal bodies/primary cilia; however, the functional role of this protein is still unknown. In this study, we established stable IMCD (mouse inner medullary collecting duct) cell lines, in which FPC was silenced by short hairpin RNA inhibition (shRNA). We showed that inhibition of FPC disrupted tubulomorphogenesis of IMCD cells grown in three-dimensional cultures. Pkhd1-silenced cells developed abnormalities in cell-cell contact, actin cytoskeleton organization, cell-ECM interactions, cell proliferation, and apoptosis, which may be mediated by dysregulation of extracellular-regulated kinase (ERK) and focal adhesion kinase (FAK) signaling. These alterations in cell function in vitro may explain the characteristics of ARPKD phenotypes in vivo.
1 Communities
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18 MeSH Terms
Molecular targets for tumour progression in gastrointestinal stromal tumours.
Koon N, Schneider-Stock R, Sarlomo-Rikala M, Lasota J, Smolkin M, Petroni G, Zaika A, Boltze C, Meyer F, Andersson L, Knuutila S, Miettinen M, El-Rifai W
(2004) Gut 53: 235-40
MeSH Terms: Chromosomal Proteins, Non-Histone, Collagen Type VIII, Cytoskeletal Proteins, DNA-Binding Proteins, Endosomal Sorting Complexes Required for Transport, Focal Adhesion Kinase 2, Gastrointestinal Neoplasms, Gene Expression, Genetic Markers, HMGB2 Protein, Humans, Microfilament Proteins, Neoplasm Proteins, Oligonucleotide Array Sequence Analysis, Phosphoproteins, Prognosis, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors
Show Abstract · Added March 5, 2014
BACKGROUND AND AIMS - The distinction between benign and malignant gastrointestinal stromal tumours (GISTs) is often unclear at the clinical and histopathology levels. GISTs are believed to arise from the stem cells of Cajal. In order to define genetic biomarkers and identify target genes related to GIST progression, we analysed and compared benign and malignant GISTs with verified follow up data using cDNA expression arrays.
METHODS - Eight genes were frequently overexpressed in malignant GISTs and their overexpression was confirmed using quantitative real time reverse transcription-polymerase chain reaction. These genes included ezrin (villin 2 (VIL2)), collagen 8 alpha 1 subunit (COL8A1), G2/mitotic specific cyclin B1 (CCNB1), high mobility group protein (HMG2), TSG101 tumour susceptibility protein, CENP-F kinetochore protein, protein tyrosine kinase 2 (FAK), and protein kinase DYRK2. To test these genes in a clinical setting, we obtained diagnostic samples of 16 additional GISTs that were classified at diagnosis as benign, malignant, and uncertain malignant potential (UMP).
RESULTS - There was remarkable gene overexpression in all malignant GISTs. Statistical analyses revealed significant correlations between overexpression of several gene pairs in malignant GISTs. We found the strongest correlations (rho>0.70) among the significant correlations (p<0.01) between CCNB1-CENP-F (rho = 0.87) and CCNB1-FAK (rho = 0.73). Gene expression of the UMP GISTs suggested two different groups. Three UMP GISTs had gene expression consistent with malignant tumours and their follow up data revealed that indeed these patients had recurrences later on. On the other hand, UMP GISTs that had low gene expression levels continued free of disease for several years.
CONCLUSIONS - These results provide insight into the oncogenesis of GISTs and suggest that testing the expression profile of a number of genes may segregate GISTs into groups of different tumour behaviour.
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20 MeSH Terms
Requirement of Ca(2+) and PKCdelta for Janus kinase 2 activation by angiotensin II: involvement of PYK2.
Frank GD, Saito S, Motley ED, Sasaki T, Ohba M, Kuroki T, Inagami T, Eguchi S
(2002) Mol Endocrinol 16: 367-77
MeSH Terms: Angiotensin II, Animals, Calcium, Cells, Cultured, Enzyme Activation, Focal Adhesion Kinase 2, Immunohistochemistry, Isoenzymes, Janus Kinase 2, Muscle, Smooth, Vascular, Phospholipid Ethers, Phosphorylation, Phosphotyrosine, Protein Kinase C, Protein Kinase C-delta, Protein Transport, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Rats, Rats, Sprague-Dawley, Receptor, Angiotensin, Type 1, Receptors, Angiotensin, Signal Transduction, Transfection, Type C Phospholipases
Show Abstract · Added December 5, 2013
In vascular smooth muscle cells, angiotensin II (AngII) stimulates association of its G protein-coupled AngII type 1 (AT(1)) receptor with Janus kinase 2 (JAK2), resulting in the activation of signal transducer and activator of transcription proteins. Although the association and activation of subsequent signal transducer and activator of transcription proteins appear to prerequire JAK2 activation, the signaling mechanism by which the AT(1) receptor activates JAK2 remains uncertain. Here, we have examined the signaling mechanism required for JAK2 activation by AngII in vascular smooth muscle cells. We found that AngII, through the AT(1) receptor, rapidly stimulated JAK2 phosphorylation at Tyr(1007/1008), the critical sites for the kinase activation. By using selective agonists and inhibitors, we demonstrated that PLC and its derived signaling molecules, phosphatidylinositol triphosphate/Ca(2+) and diacylglycerol/PKC, were essential for AngII-induced JAK2 phosphorylation. The PKC isoform required for JAK2 activation appears to be PKCdelta since a selective PKCdelta but not PKCalpha/beta inhibitor and dominant-negative PKCdelta overexpression inhibited JAK2 activation. We further examined a link between JAK2 and a Ca(2+)/PKC-sensitive tyrosine kinase, PYK2. We found that PYK2 activation by AngII requires PKCdelta, and that PYK2 associates with JAK2 constitutively. Moreover, transfection of two distinct PYK2 dominant-negative mutants markedly inhibited AngII-induced JAK2 activation. From these data we conclude that AT(1)-derived signaling molecules, specifically Ca(2+) and PKCdelta, participate in AngII-induced JAK2 activation through PYK2. These data provide a new mechanistic insight by which the hormone AngII exerts its cytokine-like actions in mediating vascular remodeling.
1 Communities
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25 MeSH Terms
Unique regulation of c-Jun N-terminal kinase by PYK2/CAK-beta in angiotensin II-stimulated vascular smooth muscle cells.
Frank GD, Eguchi S, Motley ED, Sasaki T, Inagami T
(2001) Biochem Biophys Res Commun 286: 692-6
MeSH Terms: Adenoviridae, Angiotensin II, Animals, Cells, Cultured, Focal Adhesion Kinase 2, Genetic Vectors, JNK Mitogen-Activated Protein Kinases, Leucine, Mitogen-Activated Protein Kinases, Models, Biological, Muscle, Smooth, Vascular, Mutation, Phosphorylation, Phosphotyrosine, Protein-Tyrosine Kinases, Rats, Rats, Sprague-Dawley, Transfection
Show Abstract · Added December 5, 2013
Activation of tyrosine kinases is believed to play a central role in angiotensin II (AngII) signaling. Here, we have investigated whether a tyrosine kinase, PYK2, is functionally involved in AngII-induced c-Jun N-terminal kinase (JNK) activation in vascular smooth muscle cells (VSMCs). Adenovirus expressing PYK2 kinase-inactive mutant K457A or a tyrosine phosphorylation site mutant Y402F was transfected in VSMCs. AngII-induced JNK phosphorylation was markedly enhanced by K457A, whereas it was suppressed by Y402F. Protein synthesis induced by AngII was also enhanced by K457A and inhibited by Y402F. In this regard, K457A suppressed PYK2 kinase activation by AngII, whereas it enhanced AngII-induced PYK2 Tyr(402) phosphorylation. By contrast, Y402F inhibited PYK2 Tyr(402) phosphorylation, whereas it markedly enhanced AngII-induced PYK2 kinase activation. Thus, we conclude that PYK2 kinase activity negatively regulates JNK activation and protein synthesis, whereas Tyr(402) phosphorylation positively regulates these events in AngII-stimulated VSMCs, suggesting a unique role of PYK2 in mediating vascular remodeling.
Copyright 2001 Academic Press.
1 Communities
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18 MeSH Terms