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      Integrins: Sensors of Extracellular Matrix and Modulators of Cell Function

      ,

      Cardiorenal Medicine

      S. Karger AG

      Renal function, Integrins, Cell signaling, Extracellular matrix, Migration

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          Abstract

          Integrins are a large family of transmembrane receptors for extracellular matrix (ECM) molecules. They play a critical role in organ morphogenesis, physiology and pathology, as they can modulate and control different cell functions, including adhesion, shape, polarity, growth, differentiation and motility. Integrins interact with ECM components via their extracellular domains, while their cytoplasmic domains play a pivotal role in mediating integrin-dependent cellular functions. The integrin cytoplasmic tails interact with the cytoskeleton, signaling molecules and other cellular proteins, resulting in regulation of many biological functions. In this review, we will mainly describe the role of integrins in regulating cell motility and discuss some new paradigms in integrin biology that may impact upon nephrology with respect to renal development and renal functions during both physiological and pathological events.

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          Most cited references 28

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          Molecular mechanisms controlling actin filament dynamics in nonmuscle cells.

          We review how motile cells regulate actin filament assembly at their leading edge. Activation of cell surface receptors generates signals (including activated Rho family GTPases) that converge on integrating proteins of the WASp family (WASp, N-WASP, and Scar/WAVE). WASP family proteins stimulate Arp2/3 complex to nucleate actin filaments, which grow at a fixed 70 degrees angle from the side of pre-existing actin filaments. These filaments push the membrane forward as they grow at their barbed ends. Arp2/3 complex is incorporated into the network, and new filaments are capped rapidly, so that activated Arp2/3 complex must be supplied continuously to keep the network growing. Hydrolysis of ATP bound to polymerized actin followed by phosphate dissociation marks older filaments for depolymerization by ADF/cofilins. Profilin catalyzes exchange of ADP for ATP, recycling actin back to a pool of unpolymerized monomers bound to profilin and thymosin-beta 4 that is poised for rapid elongation of new barbed ends.
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            The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly.

            Although small GTP-binding proteins of the Rho family have been implicated in signaling to the actin cytoskeleton, the exact nature of the linkage has remained obscure. We describe a novel mechanism that links one Rho family member, Cdc42, to actin polymerization. N-WASP, a ubiquitously expressed Cdc42-interacting protein, is required for Cdc42-stimulated actin polymerization in Xenopus egg extracts. The C terminus of N-WASP binds to the Arp2/3 complex and dramatically stimulates its ability to nucleate actin polymerization. Although full-length N-WASP is less effective, its activity can be greatly enhanced by Cdc42 and phosphatidylinositol (4,5) bisphosphate. Therefore, N-WASP and the Arp2/3 complex comprise a core mechanism that directly connects signal transduction pathways to the stimulation of actin polymerization.
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              Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.

              Focal and segmental glomerulosclerosis (FSGS) is a common, non-specific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension and diabetes, FSGS also appears as an isolated, idiopathic condition. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Here we present evidence implicating mutations in the gene encoding alpha-actinin-4 (ACTN4; ref. 2), an actin-filament crosslinking protein, as the cause of disease in three families with an autosomal dominant form of FSGS. In vitro, mutant alpha-actinin-4 binds filamentous actin (F-actin) more strongly than does wild-type alpha-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. Our results have implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may lead to a better understanding of the genetic basis of susceptibility to kidney damage.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2003
                July 2003
                17 November 2004
                : 94
                : 3
                : e77-e84
                Affiliations
                Department of Medicine, Division of Nephrology and Hypertension, Veterans Administration Hospital and Vanderbilt University, Nashville, Tenn., USA
                Article
                72025 Nephron Exp Nephrol 2003;94:e77–e84
                10.1159/000072025
                12902617
                © 2003 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, References: 49, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/72025
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