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A ZO-1/α5β1-Integrin Complex Regulates Cytokinesis Downstream of PKCε in NCI-H460 Cells Plated on Fibronectin  [PDF]
Saara H?m?list?, Jeroen Pouwels, Nicola de Franceschi, Markku Saari, Ylva Ivarsson, Pascale Zimmermann, Andreas Brech, Harald Stenmark, Johanna Ivaska
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070696
Abstract: Recently, we demonstrated that integrin adhesion to the extracellular matrix at the cleavage furrow is essential for cytokinesis of adherent cells. Here, we report that tight junction protein ZO-1 (Zonula Occludens-1) is required for successful cytokinesis in NCI-H460 cells plated on fibronectin. This function of ZO-1 involves interaction with the cytoplasmic domain of α5-integrin to facilitate recruitment of active fibronectin-binding integrins to the base of the cleavage furrow. In the absence of ZO-1, or a functional ZO-1/α5β1-integrin complex, proper actin-dependent constriction between daughter cells is impaired and cells fail cytokinesis. Super-resolution microscopy reveals that in ZO-1 depleted cells the furrow becomes delocalized from the matrix. We also show that PKCε-dependent phosphorylation at Serine168 is required for ZO-1 localization to the furrow and successful cell division. Altogether, our results identify a novel regulatory pathway involving the interplay between ZO-1, α5-integrin and PKCε in the late stages of mammalian cell division.
Integrin-linked kinase functions as a downstream signal of platelet-derived growth factor to regulate actin polymerization and vascular smooth muscle cell migration
Mitra Esfandiarei, Sahar Yazdi, Virginia Gray, Shoukat Dedhar, Cornelis van Breemen
BMC Cell Biology , 2010, DOI: 10.1186/1471-2121-11-16
Abstract: In the present study, we report that integrin-linked kinase controls mouse aortic smooth muscle cell migration in response to platelet-derived growth factor. We have also identified p38 mitogen activated protein kinase as a downstream signaling pathway of the integrin-linked kinase that regulates platelet-derived growth factor-induced actin polymerization and smooth muscle cell migration.This study will provide new insights into the potential therapeutic value of modulating integrin signaling in an attempt to block or delay smooth muscle cell migration and the progression of vascular diseases.The initiation and progression of intimal thickening in arterial walls is largely due to migration and subsequent proliferation of smooth muscle cells (SMCs) in the sub-intimal space in response to various stimuli including oxidized low density lipoprotein (oxLDL), circulating growth factors, and inflammatory cytokines such as platelet-derived growth factor (PDGF), tumor necrosis factor (TNF)-α, and interleukin-1 (IL-1) [1,2]. Of these, PDGF, a growth factor released by vascular SMC, endothelial cells, and platelets, has been reported as the most potent inducer of SMC migration within the injured area of the vascular wall.PDGF is a heparin-binding growth factor composed of polypeptide chains that can be assembled into homodimers (PDGF-AA, -BB) or heterodimer (PDGF-AB) structures and bind to two related cell-surface receptors with tyrosine kinase activity, PDGF receptor α and β [3-5]. In the last few years two additional homodimers PDGF-CC and PDGF-DD were also discovered [6-9]. PDGF binding to its cognate receptors results in dimerization, and subsequent auto-phosphorylation of specific tyrosine residues outside the kinase domain, creating a docking site for SH2 domain-containing signaling proteins. A large number of SH2 domain containing proteins including the phsophatidylinositol-3 kinase (PI3K), phospholipase C-γ (PLC-γ), the tyrosine phosphatase SHP-2, Ras GTPase activating
Thrombospondin-1 (TSP-1) Stimulates Expression of Integrin 6 in Human Breast Carcinoma Cells: A Downstream Modulator of TSP-1-Induced Cellular Adhesion  [PDF]
Anitha S. John,Vicki L. Rothman,George P. Tuszynski
Journal of Oncology , 2010, DOI: 10.1155/2010/645376
Abstract: Thrombospondin-1 (TSP-1) is involved in a variety of different cellular processes including cell adhesion, tumor progression, and angiogenesis. This paper reports the novel finding that TSP-1 upregulates integrin 6 subunit in human keratinocytes and human breast cancer cells resulting in increased cell adhesion and tumor cell invasion. The effect of TSP-1 on 6 subunit expression was examined in human keratinocytes and breast adenocarcinoma cell lines (MDA-MB-231) treated with TSP-1 and in TSP-1 stably transfected breast cancer cells. TSP-1 upregulated 6 message and protein in these cells as revealed by differential display, Northern and Western blot analysis and immunohistochemical localization studies. The increased expression of 6 was shown to mediate adhesion and invasion of these cells to laminin, a major component of the basement membrane and extracellular matrix (ECM). These data suggest that TSP-1 plays an integral role in the attachment of cells to the ECM facilitating cell motility and angiogenesis. 1. Introduction Adhesion to extracellular matrix (ECM) proteins is involved in almost every aspect of tumor cell metastasis including adhesion of circulating tumor cells in the vascular bed, invasion through the basement membrane, and growth of the new metastasis at a distant site [1]. In addition, contact with the ECM stimulates intracellular signaling, regulating cell attachment, migration, angiogenesis, and invasion [2–4]. Cellular adhesion is one of the major functions of thrombospondin-1(TSP-1), a component of the ECM. TSP-1 is a 450?kDa glycoprotein, originally thought to be a platelet -granule specific protein [5]. Our laboratory was the first to show that TSP-1 functions both as a tumor cell and platelet adhesive protein [6]. There are four motifs in TSP-1 which have been recognized as adhesive domains: ( ) the N-terminal heparin binding domain and its association with cell surface heparin proteoglycans, ( ) the CSVTCG sequences within the type 1 repeats and its association with CD36 and the CSVTCG receptor, ( ) the RGD sequence within the type 3 repeats and its association with the integrins, and ( ) the RFYVVMWK and IRVVM sequences in the C-terminal domain [7]. A number of cell types can attach to TSP-1 including endothelial cells and myoblasts [8–10]. In addition, many tumor cell types such as osteosarcoma cells, melanoma cells, and breast cancer cells also adhere to TSP-1 [11–13]. This suggests that TSP-1 attachment can facilitate movement through the ECM. There are several integrins that bind TSP-1. The best characterized interaction is
β3 Integrin and Src facilitate transforming growth factor-β mediated induction of epithelial-mesenchymal transition in mammary epithelial cells
Amy J Galliher, William P Schiemann
Breast Cancer Research , 2006, DOI: 10.1186/bcr1524
Abstract: β3 Integrin expression or function in MECs was manipulated by retroviral transduction of active or inactive β3 integrins, or by transient transfection of small interfering RNA (siRNA) against β3 integrin. Altered proliferation, invasion, and epithelial-mesenchymal transition (EMT) stimulated by TGF-β in control and β3 integrin manipulated MECs was determined. Src involvement in β3 integrin mediated alterations in TGF-β signaling was assessed by performing Src protein kinase assays, and by interdicting Src function pharmacologically and genetically.TGF-β stimulation induced αvβ3 integrin expression in a manner that coincided with EMT in MECs. Introduction of siRNA against β3 integrin blocked its induction by TGF-β and prevented TGF-β stimulation of EMT in MECs. β3 integrin interacted physically with the TGF-β receptor (TβR) type II, thereby enhancing TGF-β stimulation of mitogen-activated protein kinases (MAPKs), and of Smad2/3-mediated gene transcription in MECs. Formation of β3 integrin:TβR-II complexes blocked TGF-β mediated growth arrest and increased TGF-β mediated invasion and EMT. Dual β3 integrin:TβR-II activation induced tyrosine phosphorylation of TβR-II, a phosphotransferase reaction mediated by Src in vitro. Inhibiting Src activity in MECs prevented the ability of β3 integrin to induce TβR-II tyrosine phosphorylation, MAPK activation, and EMT stimulated by TGF-β. Lastly, wild-type and D119A β3 integrin expression enhanced and abolished, respectively, TGF-β stimulation of invasion in human breast cancer cells.We show that β3 integrin alters TGF-β signaling in MECs via Src-mediated TβR-II tyrosine phosphorylation, which significantly enhanced the ability of TGF-β to induce EMT and invasion. Our findings suggest that β3 integrin interdiction strategies may represent an innovative approach to re-establishing TGF-β mediated tumor suppression in progressing human breast cancers.Transforming growth factor (TGF)-β is a powerful tumor suppressor that prevents the
Integrin Targeted Imaging and Therapy
Xiaoyuan Chen
Theranostics , 2011,
Abstract: This theme issue provides an overview on the biology and pathology of various integrins as well as in-depth discussion on the use of integrin as targeting molecules for molecular imaging and molecular therapy.
Neuromuscular blockade in children
Almeida, Jo?o Fernando Louren?o de;Kalil Filho, W. Jorge;Troster, Eduardo J.;
Revista do Hospital das Clínicas , 2000, DOI: 10.1590/S0041-87812000000300007
Abstract: neuromuscular blocking agents (nmbas) have been widely used to control patients who need to be immobilized for some kind of medical intervention, such as an invasive procedure or synchronism with mechanical ventilation. the purpose of this monograph is to review the pharmacology of the nmbas, to compare the main differences between the neuromuscular junction in neonates, infants, toddlers and adults, and moreover to discuss their indications in critically ill pediatric patients. continuous improvement of knowledge about nmbas pharmacology, adverse effects, and the many other remaining unanswered questions about neuromuscular junction and neuromuscular blockade in children is essential for the correct use of these drugs. therefore, the indication of these agents in pediatrics is determined with extreme judiciousness. computorized (medline 1990-2000) and active search of articles were the mechanisms used in this review.
Neuromuscular blockade in children  [cached]
Almeida Jo?o Fernando Louren?o de,Kalil Filho W. Jorge,Troster Eduardo J.
Revista do Hospital das Clínicas , 2000,
Abstract: Neuromuscular blocking agents (NMBAs) have been widely used to control patients who need to be immobilized for some kind of medical intervention, such as an invasive procedure or synchronism with mechanical ventilation. The purpose of this monograph is to review the pharmacology of the NMBAs, to compare the main differences between the neuromuscular junction in neonates, infants, toddlers and adults, and moreover to discuss their indications in critically ill pediatric patients. Continuous improvement of knowledge about NMBAs pharmacology, adverse effects, and the many other remaining unanswered questions about neuromuscular junction and neuromuscular blockade in children is essential for the correct use of these drugs. Therefore, the indication of these agents in pediatrics is determined with extreme judiciousness. Computorized (Medline 1990-2000) and active search of articles were the mechanisms used in this review.
Integrin Trafficking and Tumor Progression
Sejeong Shin,Laura Wolgamott,Sang-Oh Yoon
International Journal of Cell Biology , 2012, DOI: 10.1155/2012/516789
Abstract: Integrins are major mediators of cancer cell adhesion to extracellular matrix. Through this interaction, integrins play critical roles in cell migration, invasion, metastasis, and resistance to apoptosis during tumor progression. Recent studies highlight the importance of integrin trafficking, endocytosis and recycling, for the functions of integrins in cancer cells. Understanding the molecular mechanisms of integrin trafficking is pivotal for understanding tumor progression and for the development of anticancer drugs.
Integrin Targeted MR Imaging
Mingqian Tan, Zheng-Rong Lu
Theranostics , 2011,
Abstract: Magnetic resonance imaging (MRI) is a powerful medical diagnostic imaging modality for integrin targeted imaging, which uses the magnetic resonance of tissue water protons to display tissue anatomic structures with high spatial resolution. Contrast agents are often used in MRI to highlight specific regions of the body and make them easier to visualize. There are four main classes of MRI contrast agents based on their different contrast mechanisms, including T1, T2, chemical exchange saturation transfer (CEST) agents, and heteronuclear contrast agents. Integrins are an important family of heterodimeric transmembrane glycoproteins that function as mediators of cell-cell and cell-extracellular matrix interactions. The overexpressed integrins can be used as the molecular targets for designing suitable integrin targeted contrast agents for MR molecular imaging. Integrin targeted contrast agent includes a targeting agent specific to a target integrin, a paramagnetic agent and a linker connecting the targeting agent with the paramagnetic agent. Proper selection of targeting agents is critical for targeted MRI contrast agents to effectively bind to integrins for in vivo imaging. An ideal integrin targeted MR contrast agent should be non-toxic, provide strong contrast enhancement at the target sites and can be completely excreted from the body after MR imaging. An overview of integrin targeted MR contrast agents based on small molecular and macromolecular Gd(III) complexes, lipid nanoparticles and superparamagnetic nanoparticles is provided for MR molecular imaging. By using proper delivery systems for loading sufficient Gd(III) chelates or superparamagnetic nanoparticles, effective molecular imaging of integrins with MRI has been demonstrated in animal models.
Integrin Targeted Delivery of Chemotherapeutics
Kai Chen, Xiaoyuan Chen
Theranostics , 2011,
Abstract: Targeted delivery of chemotherapeutics is defined in the sense, that is, to maximize the therapeutic index of a chemotherapeutic agent by strictly localizing its pharmacological activity to the site or tissue of action. Integrins are a family of heterodimeric transmembrane glycoproteins involved in a wide range of cell-to-extracellular matrix (ECM) and cell-to-cell interactions. As cell surface receptors, integrins readily interact with extracellular ligands and play a vital role in angiogenesis, leukocytes function and tumor development, which sets up integrins as an excellent target for chemotherapy treatment. The peptide ligands containing the arginine-glycine-aspartic acid (RGD), which displays a strong binding affinity and selectivity to integrins, particularly to integrin αvβ3, have been developed to conjugate with various conventional chemotherapeutic agents, such as small molecules, peptides and proteins, and nanoparticle-carried drugs for integtrin targeted therapeutic studies. This review highlights the recent advances in integrin targeted delivery of chemotherapeutic agents with emphasis on target of integrin αvβ3, and describes the considerations for the design of the diverse RGD peptide-chemotherapeutics conjugates and their major applications.
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