Molecules in focus
Syndecan-2

https://doi.org/10.1016/j.biocel.2005.08.012Get rights and content

Abstract

The members of the Syndecan family of heparan sulfate proteoglycans play diverse roles in cell adhesion and cell communication by serving as co-receptors for both cell-signaling and extracellular matrix molecules. Syndecan-2 has been implicated in the formation of specialized membrane domains and functions as a direct link between the extracellular environment and the organization of the cortical cytoplasm. Recent studies have shown that syndecan-2 is required for angiogenesis, possibly by serving as a co-receptor for vascular endothelial growth factor, and cell-to-cell signaling during development of left–right asymmetry. This unique combination of activities suggests that syndecan-2 can function as a potential drug target for the development of multi-functional, anti-cancer therapeutics.

Introduction

Syndecan-2, also called Fibroglycan, was originally biochemically characterized as one of the major heparan sulfate (HS) glycosaminoglycan (GAG)-containing cell surface proteins expressed in lung fibroblasts (Marynen, Zhang, Cassiman, Van den Berghe, & David, 1989). Syndecan-2 is one of four members of this single-pass transmembrane family in vertebrates (Kramer & Yost, 2003; Oh & Couchman, 2004) and has been observed to participate in diverse biological processes. Early work focused on the roles of syndecan-2 in cell adhesion and signaling (Tkachenko, Rhodes, & Simons, 2005). Recently, syndecan-2 has also been implicated in the progression of cancer (Beauvais & Rapraeger, 2004; Han, Park, & Oh, 2004). Furthermore, ‘knockdown’ experiments in zebrafish have demonstrated a requirement for syndecan-2 during embryonic angiogenesis (Chen, Hermanson, & Ekker, 2004). Angiogenesis or the formation of a new blood vessel from a pre-existing vessel is required for tumor growth and involves many of the same events that are important for cancer invasiveness such as the breakdown of the extracellular matrix (ECM), proliferation, and cell migration. Together, these studies suggest that syndecan-2 is capable of functioning at multiple discrete steps during tumorigenesis and metastasis by mediating tumor cell signaling, adhesion, migration, and angiogenesis.

Section snippets

Structure

The syndecan-2 core protein is linearly organized into three regions: the N-terminal ectodomain, a single-pass transmembrane domain, and the cytoplasmic tail (Fig. 1A). The syndecan-2 ectodomain contains an amino-terminal signal sequence for co-translational translocation and, in more carboxy-terminal regions, predicted GAG attachment sites. The activity of syndecan-2 is regulated by the attachment of specific HS-GAG side chains in the Golgi (Kramer & Yost, 2003). Such HS side chains are

Expression and activation

During both zebrafish and mouse development, syndecan-2 is expressed in the mesenchymal cell layer surrounding the axial blood vessels, suggesting a potential role in coordinating and organizing vascular development (Chen et al., 2004). Abundant expression of syndecan-2 in the mouse has also been noted in cells of mesenchymal origin in the kidney, lung, and stomach as well as in cells that form cartilage and bone (David et al., 1993). These studies suggest a common role for syndecan-2 in the

Biological function

Syndecan-2 and the syndecans in general can link cellular interactions with the ECM to the formation of higher order complexes at the cell membrane and the organization of cortical F-actin. The syndecan family regulates and mediates cell/substrate adhesion in part by directly binding to ECM molecules such as fibronectin (Beauvais & Rapraeger, 2004). The short cytoplasmic tail of syndecan-2 interacts with multiple proteins that serve to link the interactions with the ECM to cellular responses.

Possible therapeutic applications

Based on its diverse roles linking cell signaling and cell–ECM interactions to the cytoskeleton, syndecan-2 has a strong potential for development as a therapeutic target for treatment of cancer and other vascular-dependent disease processes. Syndecan-2 may function in lung and colon cancer cells by at least two distinct mechanisms. First, increased expression of syndecan-2 may directly relate to loss of cell/substrate interactions and contact inhibition and contribute to both the tumorigenic

Acknowledgments

We are grateful to Dr. Maura McGrail for comments on this manuscript. We thank Drs. Kenneth Kramer and H. Joseph Yost for thoughtful discussions. This work was supported in part by a grant from the National Institutes of Health to S.C.E. (GM63904).

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Present address: Iowa St University, Department of Genetics, Development and Cell Biology, Ames, IA, USA. Tel.: +1 612 656 4489; fax: +1 612 379 6580.

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