Publications by authors named "Anthony Wayne Orr"

9 Publications

  • Page 1 of 1

Sinner or Saint?: Nck Adaptor Proteins in Vascular Biology.

Front Cell Dev Biol 2021 26;9:688388. Epub 2021 May 26.

Department of Pathology and Translational Pathobiology, Louisiana State University Health - Shreveport, Shreveport, LA, United States.

The Nck family of modular adaptor proteins, including Nck1 and Nck2, link phosphotyrosine signaling to changes in cytoskeletal dynamics and gene expression that critically modulate cellular phenotype. The Nck SH2 domain interacts with phosphotyrosine at dynamic signaling hubs, such as activated growth factor receptors and sites of cell adhesion. The Nck SH3 domains interact with signaling effectors containing proline-rich regions that mediate their activation by upstream kinases. In vascular biology, Nck1 and Nck2 play redundant roles in vascular development and postnatal angiogenesis. However, recent studies suggest that Nck1 and Nck2 differentially regulate cell phenotype in the adult vasculature. Domain-specific interactions likely mediate these isoform-selective effects, and these isolated domains may serve as therapeutic targets to limit specific protein-protein interactions. In this review, we highlight the function of the Nck adaptor proteins, the known differences in domain-selective interactions, and discuss the role of individual Nck isoforms in vascular remodeling and function.
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http://dx.doi.org/10.3389/fcell.2021.688388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187788PMC
May 2021

Young at heart? Drugs of abuse cause early-onset cardiovascular disease in the young.

Heart 2021 Apr 15;107(8):604-606. Epub 2021 Feb 15.

Departments of Pathology, Cellular Biology and Anatomy, and Molecular and Cellular Physiology, LSU Health Shreveport, Shreveport, Louisiana, USA

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http://dx.doi.org/10.1136/heartjnl-2020-318856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075271PMC
April 2021

Guidance Molecules in Vascular Smooth Muscle.

Front Physiol 2018 19;9:1311. Epub 2018 Sep 19.

Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, United States.

Several highly conserved families of guidance molecules, including ephrins, Semaphorins, Netrins, and Slits, play conserved and distinct roles in tissue remodeling during tissue patterning and disease pathogenesis. Primarily, these guidance molecules function as either secreted or surface-bound ligands that interact with their receptors to activate a variety of downstream effects, including cell contractility, migration, adhesion, proliferation, and inflammation. Vascular smooth muscle cells, contractile cells comprising the medial layer of the vessel wall and deriving from the mural population, regulate vascular tone and blood pressure. While capillaries lack a medial layer of vascular smooth muscle, mural-derived pericytes contribute similarly to capillary tone to regulate blood flow in various tissues. Furthermore, pericyte coverage is critical in vascular development, as perturbations disrupt vascular permeability and viability. During cardiovascular disease, smooth muscle cells play a more dynamic role in which suppression of contractile markers, enhanced proliferation, and migration lead to the progression of aberrant vascular remodeling. Since many types of guidance molecules are expressed in vascular smooth muscle and pericytes, these may contribute to blood vessel formation and aberrant remodeling during vascular disease. While vascular development is a large focus of the existing literature, studies emerged to address post-developmental roles for guidance molecules in pathology and are of interest as novel therapeutic targets. In this review, we will discuss the roles of guidance molecules in vascular smooth muscle and pericyte function in development and disease.
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http://dx.doi.org/10.3389/fphys.2018.01311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157320PMC
September 2018

Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure.

Redox Biol 2018 04 28;14:261-271. Epub 2017 Sep 28.

Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, USA. Electronic address:

Lipid Phosphate phosphatase 3 (LPP3), encoded by the Plpp3 gene, is an enzyme that dephosphorylates the bioactive lipid mediator lysophosphatidic acid (LPA). To study the role of LPP3 in the myocardium, we generated a cardiac specific Plpp3 deficient mouse strain. Although these mice were viable at birth in contrast to global Plpp3 knockout mice, they showed increased mortality ~ 8 months. LPP3 deficient mice had enlarged hearts with reduced left ventricular performance as seen by echocardiography. Cardiac specific Plpp3 deficient mice had longer ventricular effective refractory periods compared to their Plpp3 littermates. We observed that lack of Lpp3 enhanced cardiomyocyte hypertrophy based on analysis of cell surface area. We found that lack of Lpp3 signaling was mediated through the activation of Rho and phospho-ERK pathways. There are increased levels of fetal genes Natriuretic Peptide A and B (Nppa and Nppb) expression indicating myocardial dysfunction. These mice also demonstrate mitochondrial dysfunction as evidenced by a significant decrease (P < 0.001) in the basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity as measured through mitochondrial bioenergetics. Histology and transmission electron microscopy of these hearts showed disrupted sarcomere organization and intercalated disc, with a prominent disruption of the cristae and vacuole formation in the mitochondria. Our findings suggest that LPA/LPP3-signaling nexus plays an important role in normal function of cardiomyocytes.
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http://dx.doi.org/10.1016/j.redox.2017.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635346PMC
April 2018

Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents.

J Clin Invest 2011 Aug 11;121(8):3005-23. Epub 2011 Jul 11.

Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, Texas 77843, USA.

Stroke is the leading cause of long-term disability and the third leading cause of death in the United States. While most research thus far has focused on acute stroke treatment and neuroprotection, the exploitation of endogenous brain self-repair mechanisms may also yield therapeutic strategies. Here, we describe a distinct type of stroke treatment, the naturally occurring extracellular matrix fragment of perlecan, domain V, which we found had neuroprotective properties and enhanced post-stroke angiogenesis, a key component of brain repair, in rodent models of stroke. In both rat and mouse models, Western blot analysis revealed elevated levels of perlecan domain V. When systemically administered 24 hours after stroke, domain V was well tolerated, reached infarct and peri-infarct brain vasculature, and restored stroke-affected motor function to baseline pre-stroke levels in these multiple stroke models in both mice and rats. Post-stroke domain V administration increased VEGF levels via a mechanism involving brain endothelial cell α5β1 integrin, and the subsequent neuroprotective and angiogenic actions of domain V were in turn mediated via VEGFR. These results suggest that perlecan domain V represents a promising approach for stroke treatment.
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http://dx.doi.org/10.1172/JCI46358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148740PMC
August 2011

Complex regulation and function of the inflammatory smooth muscle cell phenotype in atherosclerosis.

J Vasc Res 2010 22;47(2):168-80. Epub 2009 Oct 22.

Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, La., USA.

Vascular smooth muscle cell (SMC) phenotypic modulation plays a key role in atherosclerosis and is classically defined as a switch from a 'contractile' phenotype to a 'synthetic' phenotype, whereby genes that define the contractile SMC phenotype are suppressed and proliferation and/or migratory mechanisms are induced. There is also evidence that SMCs may take on a 'proinflammatory' phenotype, whereby SMCs secrete cytokines and express cell adhesion molecules, e.g. IL-8, IL-6, and VCAM-1, respectively, which may functionally regulate monocyte and macrophage adhesion and other processes during atherosclerosis. Factors that drive the inflammatory phenotype are not limited to cytokines but also include hemodynamic forces imposed on the blood vessel wall and intimate interaction of endothelial cells with SMCs, as well as changes in matrix composition in the vessel wall. However, it is critical to recognize that our understanding of the complex interaction of these multiple signal inputs has only recently begun to shed light on mechanisms that regulate the inflammatory SMC phenotype, primarily through models that attempt to recreate this environment ex vivo. The goal of this review is to summarize our current knowledge in this area and identify some of the key unresolved challenges and questions requiring further study.
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http://dx.doi.org/10.1159/000250095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842170PMC
March 2010

Thrombospondin induces RhoA inactivation through FAK-dependent signaling to stimulate focal adhesion disassembly.

J Biol Chem 2004 Nov 13;279(47):48983-92. Epub 2004 Sep 13.

Department of Pathology, Division of Molecular and Cellular Pathology and the Cell Adhesion and Matrix Research Center, University of Alabama, Birmingham, Alabama 35294-9340, USA.

Cells utilize dynamic interactions with the extracellular matrix to adapt to changing environmental conditions. Thrombospondin 1 (TSP1) induces focal adhesion disassembly and cell migration through a sequence (hep I) in its heparin-binding domain signaling through the calreticulin-low density lipoprotein receptor-related protein receptor complex. This involves the Galphai-dependent activation of ERK and phosphoinositide (PI) 3-kinase, both of which are required for focal adhesion disassembly. Focal adhesion kinase (FAK) regulates adhesion dynamics, acting in part by modulating RhoA activity, and FAK is implicated in ERK and PI 3-kinase activation. In this work, we sought to determine the role of FAK in TSP1-induced focal adhesion disassembly. TSP1/hep I does not stimulate focal adhesion disassembly in FAK knockout fibroblasts, whereas re-expressing FAK rescues responsiveness. Inhibiting FAK signaling through FRNK or FAK Y397F expression in endothelial cells also abrogates this response. TSP1/hep I stimulates a transient increase in FAK phosphorylation that requires calreticulin and Galphai, but not ERK or PI 3-kinase. Hep I does not activate ERK or PI 3-kinase in FAK knockout fibroblasts, suggesting activation occurs downstream of FAK. TSP1/hep I stimulates RhoA inactivation with kinetics corresponding to focal adhesion disassembly in a FAK, ERK, and PI 3-kinase-dependent manner. Furthermore, hep I does not stimulate focal adhesion disassembly in cells expressing constitutively active RhoA, suggesting that RhoA inactivation is required for this response. This is the first work to illustrate a connection between FAK phosphorylation in response to a soluble factor and RhoA inactivation, as well as the first report of PI 3-kinase and ERK in FAK regulation of RhoA activity.
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http://dx.doi.org/10.1074/jbc.M404881200DOI Listing
November 2004

Low density lipoprotein receptor-related protein is a calreticulin coreceptor that signals focal adhesion disassembly.

J Cell Biol 2003 Jun;161(6):1179-89

Department of Pathology, Division of Molecular and Cellular Pathology and The Cell Adhesion and Matrix Research Center, University of Alabama at Birmingham, VH 668 1530, 3rd Ave. South, Birmingham, AL 35294-0019, USA.

Thrombospondin (TSP) signals focal adhesion disassembly (the intermediate adhesive state) through interactions with cell surface calreticulin (CRT). TSP or a peptide (hep I) of the active site induces focal adhesion disassembly through binding to CRT, which activates phosphoinositide 3-kinase (PI3K) and extracellular signal-related kinase (ERK) through Galphai2 proteins. Because CRT is not a transmembrane protein, it is likely that CRT signals as part of a coreceptor complex. We now show that low density lipoprotein receptor-related protein (LRP) mediates focal adhesion disassembly initiated by TSP binding to CRT. LRP antagonists (antibodies, receptor-associated protein) block hep I/TSP-induced focal adhesion disassembly. LRP is necessary for TSP/hep I signaling because TSP/hep I is unable to stimulate focal adhesion disassembly or ERK or PI3K signaling in fibroblasts deficient in LRP. LRP is important in TSP-CRT signaling, as shown by the ability of hep I to stimulate association of Galphai2 with LRP. The isolated proteins LRP and CRT interact, and LRP and CRT are associated with hep I in molecular complexes extracted from cells. These data establish a mechanism of cell surface CRT signaling through its coreceptor, LRP, and suggest a novel function for LRP in regulating cell adhesion.
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http://dx.doi.org/10.1083/jcb.200302069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172996PMC
June 2003

Thrombospondin stimulates focal adhesion disassembly through Gi- and phosphoinositide 3-kinase-dependent ERK activation.

J Biol Chem 2002 Jun 28;277(23):20453-60. Epub 2002 Mar 28.

Department of Pathology, University of Alabama, Birmingham, Alabama 35294-0019, USA.

The matricellular protein thrombospondin (TSP) stimulates stress fiber and focal adhesion disassembly through a sequence (hep I) in its heparin-binding domain. TSP/hep I signals focal adhesion disassembly by binding cell surface calreticulin (CRT) and activating phosphoinositide 3-kinase (PI3K). However, other components of this signaling pathway have not been identified. We now show that TSP induces focal adhesion disassembly through activation of pertussis toxin (PTX)-sensitive G proteins and ERK phosphorylation. PTX pretreatment inhibits TSP/hep I-mediated focal adhesion disassembly as well as PI3K activation. In addition, membrane-permeable Galpha(i2)- and Gbetagamma-blocking peptides inhibit hep I-mediated focal adhesion disassembly. Hep I stimulates a transient increase in ERK activation, which is abrogated by both PTX and PI3K inhibitors. Inhibiting ERK activation with MEK inhibitors blocks hep I-mediated focal adhesion disassembly, indicating that ERK activation is required for cytoskeletal reorganization. G protein signals and ERK phosphorylation are induced by TSP binding to cell surface CRT, because CRT null mouse embryonic fibroblasts (MEF) fail to stimulate ERK phosphorylation in response to TSP/hep I treatment. These data show that G(i) protein and ERK, in concert with PI3K, are stimulated by TSP.CRT interactions at the cell surface to induce de-adhesive changes in the cytoskeleton.
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http://dx.doi.org/10.1074/jbc.M112091200DOI Listing
June 2002
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