A5000476093- Nitric Oxide and Endothelin Effects
- Angiogenesis and VEGF in Cancer
- Renin-Angiotensin System Studies
- Receptor Mechanisms and Signaling
- Caveolin-1 and cellular processes
- Eicosanoids and Hypertension Pharmacology
- Phagocytosis and Immune Regulation
- Cell Adhesion Molecules Research
- Cancer, Hypoxia, and Metabolism
- Ion Transport and Channel Regulation
- Sphingolipid Metabolism and Signaling
- Pancreatic and Hepatic Oncology Research
- Pulmonary Hypertension Research and Treatments
- ATP Synthase and ATPases Research
- Pancreatic function and diabetes
- Hormonal Regulation and Hypertension
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Heat shock proteins research
- Signaling Pathways in Disease
- Electron Spin Resonance Studies
- Protein Tyrosine Phosphatases
- Neuropeptides and Animal Physiology
- Erythrocyte Function and Pathophysiology
- RNA Interference and Gene Delivery
- interferon and immune responses
Université de Montréal
2014-2025
Montreal Clinical Research Institute
2003-2012
Augusta University
2011
Walker (United States)
2011
Center for Vascular Biology Research
2011
Montreal Heart Institute
2010
Hôtel-Dieu de Québec
2009
Université Laval
2009
Yale University
1999-2004
University of Pennsylvania
2002
Endothelial nitric oxide synthase (eNOS) is important for cardiovascular homeostasis, vessel remodeling, and angiogenesis. Given the impact of endothelium- derived (NO) in vascular biology, much work past several years has focused on control NO synthesis by regulatory proteins that influence its function. Indeed calcium-activated calmodulin regulation NOS activity. Herein we discuss why other proteins, addition to calmodulin, are necessary eNOS summarize biology negative positive regulators...
The activity of endothelial nitric-oxide synthase (eNOS) is regulated by its subcellular localization, phosphorylation and through interaction with different proteins. association eNOS caveolin-1 (Cav) believed to maintain in an inactive state; however, increased heat shock protein 90 (hsp90) observed following activation. In this study, we investigate the relationship between caveolin hsp90 as opposing regulatory proteins on function. Immunoprecipitation Cav-1 from bovine lung microvascular...
Vascular endothelial growth factor (VEGF) utilizes a phosphoinositide 3-kinase (PI 3-kinase)/Akt signaling pathway to protect cells from apoptotic death. Here we show that PI 3-kinase/Akt promotes cell survival by inhibiting p38 mitogen-activated protein kinase (MAPK)-dependent apoptosis. Blockade of the or Akt pathways in conjunction with serum withdrawal stimulates p38-dependent also led enhanced VEGF activation and In this context, pro-apoptotic effect is attenuated MAPK inhibitor...
Sphingosine 1-phosphate (SPP) binds to members of the endothelial differentiation gene family (EDG) receptors and leads diverse signaling events including cell survival, growth, migration differentiation. However, mechanisms how SPP activates these proangiogenic pathways are poorly understood. Here we show that signals through EDG-1 receptor heterotrimeric G protein Gi, leading activation serine/threonine kinase Akt phosphorylation substrate, nitric-oxide synthase (eNOS). Inhibition...
The subcellular localization of endothelial nitric-oxide synthase (eNOS) is critical for optimal coupling extracellular stimulation to nitric oxide production. Because eNOS activated by Akt-dependent phosphorylation produce (NO), we determined the distribution phosphorylated on serine 1179 using a variety methodologies. Based sucrose gradient fractionation, phosphorylated-eNOS (P-eNOS) was found in both caveolin-1-enriched membranes and intracellular domains. Co-transfection with Akt cells...
AXL is activated by its ligand GAS6 and expressed in triple-negative breast cancer cells. In the current study, we report expression HER2-positive (HER2+) cancers where it correlates with poor patient survival. Using murine models of HER2+ cancer, Axl, but not Gas6, was found to be essential for metastasis. We determined that required intravasation, extravasation, growth at metastatic site. displaying epithelial-to-mesenchymal transition (EMT) signatures contributes sustain EMT. Interfering...
Significance Diabetic retinopathy is a major cause of blindness in the working population. The most common visual impairment diabetic patients macular edema (DME). Roughly 40% with DME respond poorly to anti-VEGF therapies, which are standard care. Here we provide mechanistic insight for critical role NOTCH1 signaling compromising endothelial junction integrity during diabetes. Besides activating canonical transcriptional pathways, find that also provokes disruption junctions via...
During gastrulation, Wnt-β-catenin signaling dictates lineage bifurcation generating different mesoderm cell types. However, the specific role of Wnt receptors in specification remains elusive. Using selective Frizzled (FZD) and LRP5/6 antibody-based agonists, we examined FZD receptors' function during directed differentiation human pluripotent stem cells (hPSCs). We found that FZD2 FZD7 are expressed at membrane hPSCs their activation triggers β-catenin with kinetics, thereby influencing...
The 894G→T polymorphism within exon 7 of the human endothelial nitric-oxide synthase (eNOS) gene codes for glutamate or aspartate, respectively, at residue 298 and has been associated with several diseases cardiovascular origin. A recent report indicates that Asp298-eNOS (E298D) is cleaved intracellularly to 100- 35-kDa fragments, suggesting a mechanism reduced function. Here we have documented precise cleavage site E298D variant as unique aspartyl-prolyl (Asp298–Pro299) bond not seen in...
Nitric oxide (NO) release from endothelial cells, via NO synthase (eNOS) activation, is central to the proangiogenic actions of vascular growth factor (VEGF). VEGF signaling eNOS principally mediated by an Akt-dependent phosphorylation and increased association molecular chaperone, heat-shock protein 90 kDa (Hsp90). Herein, we report that VEGFR-2 activation induces tyrosine receptor 2 (VEGFR-2)-associated Hsp90beta. Tyrosine Hsp90beta in response dependent on internalization Src kinase...
The Hedgehog signaling pathway is involved in early embryonic patterning as well cancer; however, little known about the subcellular localization of receptor complex Patched and Smoothened. Since Hh has been found lipid rafts Drosophila, we hypothesized that Smoothened might also be these cholesterol-rich microdomains. In this study, demonstrate both are caveolin-1-enriched/raft Immunoprecipitation studies show specifically interacts with caveolin-1, whereas does not. Fractionation...
Ligand-stimulated degradation of receptor tyrosine kinase (RTK) is an important regulatory step signal transduction. The vascular endothelial growth factor (VEGF) Flk-1/KDR responsible for the VEGF-stimulated nitric oxide (NO) production from cells. Cellular mechanisms mediating negative regulation Flk-1 signaling in cells have not been investigated. Here we show that rapidly down-regulated following VEGF stimulation bovine aortic (BAECs). Consequently, pretreatment prevents any further...
Myoferlin and dysferlin are members of the ferlin family membrane proteins. Recent studies have shown that mutation or genetic disruption myoferlin promotes muscular dystrophy-related phenotypes in mice, which result impaired plasma integrity. However, no biological functions been ascribed to non-muscle tissues. Herein, using a proteomic analysis endothelial cell (EC) caveolae/lipid raft microdomains we identified these domains show is highly expressed ECs vascular The loss results lack...
Objective— Sphingosine-1-phosphate (S1P) is a potent bioactive phospholipid responsible for variety of vascular cell responses. Hypoxia-inducible factor-1 (HIF-1) transcriptional activator genes essential adaptation to low oxygen. S1P and HIF-1 are both important mediators responses such as migation, proliferation, survival. Studies have shown that nonhypoxic stimuli can activate in oxygenated conditions. Here, we attempt determine whether modulate the activation HIF-1. Methods Results— We...
Excessive synthesis of reactive oxygen species contributes to the pathology many human diseases and originates from changes in expression posttranslational regulation transmembrane NADPH oxidases (Noxes). Nox5 is a novel Nox isoform whose activity regulated by intracellular calcium levels. We have reported that calcium-sensitivity can also be modulated direct phosphorylation. However, kinases phosphorylate not been identified, thus, goal this study was determine whether calcium-activated...
The receptor tyrosine kinase Axl contributes to cell migration and invasion. Expression of correlates with metastatic progression in cancer patients, yet the specific signaling events promoting invasion downstream are poorly defined. Herein, we report Elmo scaffolds be direct substrates binding partners Axl. proteins established interact Dock family guanine nucleotide exchange factors control Rac-mediated cytoskeletal dynamics. Proteomics mutagenesis studies reveal that phosphorylates...
Abstract Aberrant expression of receptor tyrosine kinase AXL is linked to metastasis. can be activated by its ligand GAS6 or other kinases, but the signaling pathways conferring metastatic activity are unknown. Here, we define AXL-regulated phosphoproteome in breast cancer cells. We reveal that stimulates phosphorylation a network focal adhesion (FA) proteins, culminating faster FA disassembly. Mechanistically, phosphorylates NEDD9, leading binding CRKII which turn associates with and...
Significance A significant pool of HER2 + breast cancer patients are either unresponsive or become resistant to standards care. New therapeutic approaches exploiting the tumor microenvironment, including immunotherapies, attractive. Hypoxia shapes microenvironment toward therapy resistance and metastasis. Here, we report a role for AXL receptor tyrosine kinase in hypoxic response by promoting HIF-1α expression. Interfering with Axl preclinical model normalizes blood vessels promotes...