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J. Biol. Chem., Vol. 283, Issue 43, 29322-29330, October 24, 2008

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Structural and Cell Adhesion Properties of Zebrafish Syndecan-4 Are Shared with Higher Vertebrates^*

James R. Whiteford¹, Sunggeon Ko, Weontae Lee, and John R. Couchman¹²

From the Biomedicine Institute, University of Copenhagen, Biocenter, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark and the Department of Biochemistry and Molecular Biophysics Laboratory, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea

The syndecan proteoglycans are an ancient class of receptor, bearing heparan sulfate chains that interact with numerous potential ligands including growth factors, morphogens, and extracellular matrix molecules. The single syndecan of invertebrates appears not to have cell adhesion roles, but these have been described for mammalian paralogues, especially syndecan-4. This member is best understood in terms of interactions, signaling, and structure of its cytoplasmic domain. The zebrafish homologue of syndecan-4 has been genetically linked to cell adhesion and migration in zebrafish embryos, but no molecular and cellular studies have been reported. Here it is demonstrated that key functional attributes of syndecan-4 are common to both zebrafish and mammalian homologues. These include glycosaminoglycan substitution, a NXIP motif in the extracellular domain that promotes integrin-mediated cell adhesion, and a transmembrane GXXXG motif that promotes dimer formation. In addition, despite some amino acid substitutions in the cytoplasmic domain, its ability to form twisted clamp dimers is preserved, as revealed by nuclear magnetic resonance spectroscopy. This technique also showed that phosphatidylinositol 4,5-bisphosphate can interact with the zebrafish syndecan-4 cytoplasmic domain, and that the molecule in its entirety supports focal adhesion formation, and complements the murine null cells to restore a normal actin cytoskeleton identically to the rat homologue. Therefore, the cell adhesion properties of syndecan-4 are consistent across the vertebrate spectrum and reflect an early acquisition of specialization after syndecan gene duplication events at the invertebrate/early chordate boundary.

Received for publication, May 8, 2008 , and in revised form, August 19, 2008.

^* This work was supported in part by Wellcome Trust Programme Grant 065940 (to J. R. C.). This work was also supported by a Korea Science and Engineering Foundation (KOSEF) Grant R01-2007-000-10161-0 funded by the Korea government (MOST) (to W. L.). 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 Fig. S1.

¹ Supported by the Danish National Research Foundation.

² To whom correspondence should be addressed: Biomedicine Institute, University of Copenhagen, Biocenter, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark. Tel.: 004535325670; E-mail: john.couchman{at}bric.dk.

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