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J. Biol. Chem., Vol. 282, Issue 48, 34929-34937, November 30, 2007

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A Peptide Derived from Tenascin-C Induces β1 Integrin Activation through Syndecan-4^*

Yohei Saito, Hisae Imazeki, Shogo Miura, Tomohisa Yoshimura, Hiroaki Okutsu, Yosei Harada, Toshiyuki Ohwaki, Osamu Nagao, Sadahiro Kamiya, Ryo Hayashi, Hiroaki Kodama, Hiroshi Handa^¶, Toshimichi Yoshida^||, and Fumio Fukai¹

From the Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan, the Department of Biochemistry, Faculty of Science and Engineering, Saga University, Saga 849-0922, Japan, the ^¶Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan, and the ^||Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Mie 514-8507, Japan

Tenascin-C (TN-C) is unique for its cell adhesion modulatory function. We have shown that TNIIIA2, a synthetic 22-mer peptide derived from TN-C, stimulated β1 integrin-mediated cell adhesion of nonadherent and adherent cell types, by inducing activation of β1 integrin. The active site of TNIIIA2 appeared cryptic in the TN-C molecule but was exposed by MMP-2 processing of TN-C. The following results suggest that cell surface heparan sulfate (HS) proteoglycan (HSPG), including syndecan-4, participated in TNIIIA2-induced β1 integrin activation: 1) TNIIIA2 bound to cell surface HSPG via its HS chains, as examined by photoaffinity labeling; 2) heparitinase I treatment of cells abrogated β1 integrin activation induced by TNIIIA2; 3) syndecan-4 was isolated by affinity chromatography using TNIIIA2-immobilized beads; 4) small interfering RNA-based down-regulation of syndecan-4 expression reduced TNIIIA2-induced β1 integrin activation, and consequent cell adhesion to fibronectin; 5) overexpression of syndecan-4 core protein enhanced TNIIIA2-induced activation of β1 integrin. However, treatments that targeted the cytoplasmic region of syndecan-4, including ectopic expression of its mutant truncated with the cytoplasmic domains and treatment with protein kinase C inhibitor Gö6976, did not influence the TNIIIA2 activity. These results suggest that a TNIIIA2-related matricryptic site of the TN-C molecule, exposed by MMP-2 processing, may have bound to syndecan-4 via its HS chains and then induced conformational change in β1 integrin necessary for its functional activation. A lateral interaction of β1 integrin with the extracellular region of the syndecan-4 molecule may be involved in this conformation change.

Received for publication, July 9, 2007 , and in revised form, September 21, 2007.

^* This work was supported by Grant-in-aid 17590074 for Scientific Research provided by the Ministry of Education, Science, and Culture of Japan, and by the Vehicle Racing Commemorative Foundation. 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 Figs. S1–S3 and Table S1.

¹ To whom correspondence should be addressed: Dept. of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-Shi, Chiba 278-8510, Japan. Tel./Fax: 81-4-7121-3619; E-mail: fukai{at}rs.noda.tus.ac.jp.