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J. Biol. Chem., Vol. 283, Issue 30, 20937-20947, July 25, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/30/20937    most recent M801763200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Telci, D. Articles by Griffin, M. PubMed PubMed Citation Articles by Telci, D. Articles by Griffin, M. Related Collections Related Webpages Social Bookmarking                      What's this?

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Fibronectin-Tissue Transglutaminase Matrix Rescues RGD-impaired Cell Adhesion through Syndecan-4 and β₁ Integrin Co-signaling^*

Dilek Telci, Zhuo Wang, Xiaoling Li, Elisabetta A. M. Verderio^¶, Martin J. Humphries^||, Manuela Baccarini^**, Huveyda Basaga, and Martin Griffin¹

From the School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B47ET, United Kingdom, Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul 34956, Turkey, ^¶School of Biomedical and Natural Sciences, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, United Kingdom, ^||School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom, and ^**Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, Campus Vienna Biocenter, 1030 Vienna, Austria

Heterotropic association of tissue transglutaminase (TG2) with extracellular matrix-associated fibronectin (FN) can restore the adhesion of fibroblasts when the integrin-mediated direct binding to FN is impaired using RGD-containing peptide. We demonstrate that the compensatory effect of the TG-FN complex in the presence of RGD-containing peptides is mediated by TG2 binding to the heparan sulfate chains of the syndecan-4 cell surface receptor. This binding mediates activation of protein kinase C (PKC) and its subsequent interaction with β₁ integrin since disruption of PKC binding to β₁ integrins with a cell-permeant competitive peptide inhibits cell adhesion and the associated actin stress fiber formation. Cell signaling by this process leads to the activation of focal adhesion kinase and ERK1/2 mitogen-activated protein kinases. Fibroblasts deficient in Raf-1 do not respond fully to the TG-FN complex unless either the full-length kinase competent Raf-1 or the kinase-inactive domain of Raf-1 is reintroduced, indicating the involvement of the Raf-1 protein in the signaling mechanism. We propose a model for a novel RGD-independent cell adhesion process that could be important during tissue injury and/or remodeling whereby TG-FN binding to syndecan-4 activates PKC leading to its association with β₁ integrin, reinforcement of actin-stress fiber organization, and MAPK pathway activation.

Received for publication, March 5, 2008 , and in revised form, April 28, 2008.

^* This work was supported in part by Scientific and Technological Research Council of Turkey SBAG Grant 104S606. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. 1–3.

¹ To whom correspondence should be addressed. Tel.: 121-204-3942; Fax: 121-204-5142; E-mail: M.Griffin{at}aston.ac.uk.

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