αV-Integrins Are Required for Mechanotransduction in MDCK Epithelial Cells

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Abstract

The properties of epithelial cells within tissues are regulated by their immediate microenvironment, which consists of neighboring cells and the extracellular matrix (ECM). Integrin heterodimers orchestrate dynamic assembly and disassembly of cell-ECM connections and thereby convey biochemical and mechanical information from the ECM into cells. However, the specific contributions and functional hierarchy between different integrin heterodimers in the regulation of focal adhesion dynamics in epithelial cells are incompletely understood. Here, we have studied the functions of RGD-binding αV-integrins in a Madin Darby Canine Kidney (MDCK) cell model and found that αV-integrins regulate the maturation of focal adhesions (FAs) and cell spreading. αV-integrin-deficient MDCK cells bound collagen I (Col I) substrate via α2β1-integrins but failed to efficiently recruit FA components such as talin, focal adhesion kinase (FAK), vinculin and integrin-linked kinase (ILK). The apparent inability to mature α2β1-integrin-mediated FAs and link them to cellular actin cytoskeleton led to disrupted mechanotransduction in αV-integrin deficient cells seeded onto Col I substrate.

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Most cited references 52

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Tensional homeostasis and the malignant phenotype.

Matthew J. Paszek, Nastaran Zahir, Kandice R. Johnson … (2005)

Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.

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RGD and other recognition sequences for integrins.

E Ruoslahti (1996)

Proteins that contain the Arg-Gly-Asp (RGD) attachment site, together with the integrins that serve as receptors for them, constitute a major recognition system for cell adhesion. The RGD sequence is the cell attachment site of a large number of adhesive extracellular matrix, blood, and cell surface proteins, and nearly half of the over 20 known integrins recognize this sequence in their adhesion protein ligands. Some other integrins bind to related sequences in their ligands. The integrin-binding activity of adhesion proteins can be reproduced by short synthetic peptides containing the RGD sequence. Such peptides promote cell adhesion when insolubilized onto a surface, and inhibit it when presented to cells in solution. Reagents that bind selectively to only one or a few of the RGD-directed integrins can be designed by cyclizing peptides with selected sequences around the RGD and by synthesizing RGD mimics. As the integrin-mediated cell attachment influences and regulates cell migration, growth, differentiation, and apoptosis, the RGD peptides and mimics can be used to probe integrin functions in various biological systems. Drug design based on the RGD structure may provide new treatments for diseases such as thrombosis, osteoporosis, and cancer.

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Integrin-regulated FAK-Src signaling in normal and cancer cells.

Satyajit K. Mitra, David Schlaepfer (2006)

Integrins can alter cellular behavior through the recruitment and activation of signaling proteins such as non-receptor tyrosine kinases including focal adhesion kinase (FAK) and c-Src that form a dual kinase complex. The FAK-Src complex binds to and can phosphorylate various adaptor proteins such as p130Cas and paxillin. In normal cells, multiple integrin-regulated linkages exist to activate FAK or Src. Activated FAK-Src functions to promote cell motility, cell cycle progression and cell survival. Recent studies have found that the FAK-Src complex is activated in many tumor cells and generates signals leading to tumor growth and metastasis. As both FAK and Src catalytic activities are important in promoting VEGF-associated tumor angiogenesis and protease-associated tumor metastasis, support is growing that FAK and Src may be therapeutically relevant targets in the inhibition of tumor progression.

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Author and article information

Contributors

Adam J. Engler: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 19 August 2013

Volume: 8

Issue: 8

Electronic Location Identifier: e71485

Affiliations

[1 ]Biocenter Oulu, Oulu Center for Cell-Matrix Research, Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland

[2 ]Leibniz Institute of Polymer Research Dresden, Institute of Biofunctional Polymer Materials, Dresden, Germany

[3 ]ETH Zürich, Department of Biosystems Science and Engineering, Basel, Switzerland

[4 ]Biotechnology Center, Dresden University of Technology, Dresden, Germany

[5 ]Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America

[6 ]Department of Surgery, Committee on Cell Physiology, and Committee on Molecular Pathogenesis and Molecular Medicine, The University of Chicago, Chicago, Illinois, United States of America

University of California, San Diego, United States of America

Author notes

* E-mail: aki.manninen@ 123456oulu.fi

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: AM TT SM JF DM JM KM. Performed the experiments: TT SM JF NS AM. Analyzed the data: TT SM JF NS DM AM. Contributed reagents/materials/analysis tools: KM JM CW. Wrote the paper: AM TT JF DM.

Article

Publisher ID: PONE-D-13-07044

DOI: 10.1371/journal.pone.0071485

PMC ID: 3747215

PubMed ID: 23977051

SO-VID: 39d15e8f-0e8b-4833-9473-11ca2d357eb9

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 6 February 2013

Date accepted : 29 June 2013

Page count

Pages: 15

Funding

This work was supported by Academy of Finland Grants (114330, 135560 and 140974), by Federal Ministry of Education and Research, Germany, by Biocenter Finland, and by the Sigrid Juselius Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

αV-Integrins Are Required for Mechanotransduction in MDCK Epithelial Cells

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Gamma Delta T cells

Most cited references 52

Tensional homeostasis and the malignant phenotype.

RGD and other recognition sequences for integrins.

Integrin-regulated FAK-Src signaling in normal and cancer cells.

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