The International Journal of Biochemistry & Cell Biology
Molecules in focusSyndecan-2
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).
References (20)
- et al.
Syndecan-2 is essential for angiogenic sprouting during zebrafish development
Blood
(2004) - et al.
Inducible expression of the cell surface heparan sulfate proteoglycan syndecan-2 (fibroglycan) on human activated macrophages can regulate fibroblast growth factor action
J. Biol. Chem.
(1999) - et al.
EphB/syndecan-2 signaling in dendritic spine morphogenesis
Neuron
(2001) - et al.
Syndecan-2 induces filopodia by active cdc42Hs
Exp. Cell Res.
(1999) - et al.
P120-GAP associated with syndecan-2 to function as an active switch signal for src upon transformation with oncogenic ras
Biochem. Biophys. Res. Commun.
(2005) - et al.
PKCgamma regulates syndecan-2 inside-out signaling during xenopus left-right development
Cell
(2002) - et al.
Ectodermal syndecan-2 mediates left-right axis formation in migrating mesoderm as a cell-nonautonomous Vg1 cofactor
Dev. Cell
(2002) - et al.
Participation of syndecan-2 in the induction of stress fiber formation in cooperation with integrin alpha5beta1: Structural characteristics of heparan sulfate chains with avidity to COOH-terminal heparin-binding domain of fibronectin
Exp. Cell Res.
(2000) - et al.
Partial primary structure of the 48- and 90-kilodalton core proteins of cell surface-associated heparan sulfate proteoglycans of lung fibroblasts prediction of an integral membrane domain and evidence for multiple distinct core proteins at the cell surface of human lung fibroblasts
J. Biol. Chem.
(1989) - et al.
Syndecans-2 and -4; close cousins, but not identical twins
Mol. Cells
(2004)
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2022, Matrix BiologyCitation Excerpt :Shed syndecan-2-bound FGF-2 interacts more efficiently with the FGF receptor than FGF alone. As a result, shed syndecan-2 can enhance angiogenesis via the FGF receptor signaling pathway [51,52]. Consistently, we found that shed syndecan-2 increased the proliferation, migration and tube formation of HUVECs (Fig. 7b–d).
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2019, Pharmacology and TherapeuticsCitation Excerpt :AG73 is a ligand for syndecans, a transmembrane heparan sulfate proteoglycan (Carey, 1997; Hoffman et al., 2001). Syndecan-2 is highly expressed in various cancer cell lines and plays a role in angiogenesis (Essner, Chen, & Ekker, 2006; Fears and Woods, 2006; Noguer, Villena, Lorita, Vilaró, & Reina, 2009; Tkachenko, Rhodes, & Simons, 2005). We hypothesized that novel delivery systems could be developed using AG73 as a moiety to target cancer cells (Figs. 2, 3).
Syndecan transmembrane domain modulates intracellular signaling by regulating the oligomeric status of the cytoplasmic domain
2018, Cellular SignallingCitation Excerpt :In a similar manner, the stability of the transmembrane domain association influences the basal activity of each integrin, suggesting that differences in the transmembrane domains have significant effects on the conformational free energies of integrins [45,46]. Interestingly, the unique dimeric conformation of the syndecan-2 cytoplasmic domain is associated with unique structural characteristics in the C-terminal region of the transmembrane domain where it directly connects to the cytoplasmic domain [41]. This unique structure of the C-terminal region was altered in a syndecan-2 mutant sequence harboring Ile in place of Phe167, which exhibited defects in the interaction of its cytoplasmic domain with intracellular components.
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