Mini reviewMolecular functions of syndecan-1 in disease
Introduction
Syndecans comprise a major family of cell surface heparan sulfate proteoglycans (HSPGs) (Bernfield et al., 1999, Park et al., 2000b, Couchman, 2010). Syndecans are expressed on the surface of all adherent cells and on many non-adherent cells. The mammalian syndecan family consists of 4 members, each encoded by distinct genes. Although cloning of the first syndecan, syndecan-1, was reported in 1989 (Saunders et al., 1989), its existence was known prior to this report as the Bernfield (Rapraeger and Bernfield, 1983) and Hook (Kjellen et al., 1981) groups have identified an HSPG intercalated in the plasma membrane of mouse mammary gland epithelial cells and rat hepatocytes, respectively. This HSPG was found to be expressed predominantly on the basolateral surface of epithelial cells (Rapraeger et al., 1986, Hayashi et al., 1987), bind to extracellular matrix (ECM) components, such as collagens I, III and V (Koda et al., 1985), fibronectin (Saunders and Bernfield, 1988) and thrombospondin (Sun et al., 1989), and associate with the actin cytoskeleton (Rapraeger et al., 1986). Because these properties indicated that this HSPG is well positioned to function as an anchor that stabilizes the morphology of epithelial sheets by connecting the ECM to the intracellular cytoskeleton, the name ‘syndecan’ (from the Greek syndein, which means to bind together) was given to this HSPG. Subsequently, syndecan-2 (fibroglycan) (Marynen et al., 1989, Pierce et al., 1992), syndecan-3 (N-syndecan) (Carey et al., 1992, Gould et al., 1992), and syndecan-4 (amphiglycan/ryudocan) (David et al., 1992, Kojima et al., 1992) were identified.
Syndecans are type I transmembrane proteins, consisting of an extracellular domain where heparan sulfate (HS) chains attach distally to the plasma membrane, followed by the signature transmembrane and cytoplasmic domains which are highly homologous among the different syndecans and across species. The transmembrane domain contains a GxxxG dimerization motif and mediates both homotypic and heterotypic dimerization of syndecans (Dews and Mackenzie, 2007). The syndecan cytoplasmic domain contains several conserved signaling and scaffolding motifs, including one invariant Ser, three invariant Tyr, and a Glu-Phe-Tyr-Ala PDZ binding domain at the C-terminus (Bernfield et al., 1999, Lambaerts et al., 2009, Couchman, 2010). Syndecans are expressed on different cells and locations at different times and levels (Bernfield et al., 1992). In adult tissues, syndecan-1 is predominantly expressed by both simple and stratified epithelial cells and plasma cells, although it is expressed at a lower level in several other cell types and its expression can be induced in these cells. Syndecan-2 is typically expressed by endothelial cells and mesenchymal cells, whereas syndecan-3 expression is mostly restricted to neural crest-derived cells. Syndecan-4 is expressed ubiquitously, but it is expressed at lower levels than other co-expressed syndecans on any given cell type.
Syndecans bind to and regulate many HS- and heparin-binding molecules (Bernfield et al., 1999, Fears and Woods, 2006). However, much debate surrounds the biological significance and specificity of syndecan interactions due to the large number of potential ligands. Available data indicate that syndecans can regulate the biological activity of ligands by affecting their stability, conformation, oligomerization, or compartmentalization (Park et al., 2000b). Further, although all syndecans contain the primary ligand-binding HS chains, they show distinct temporal and spatial expression patterns (Hayashi et al., 1987, Kim et al., 1994) and, thus, are likely to function specifically in vivo. In addition, syndecans can bind to ligands through their core protein (McFall and Rapraeger, 1998, Chen et al., 2004, Hayashida et al., 2006, Dews and Mackenzie, 2007, Beauvais et al., 2009, Couchman, 2010, Purushothaman et al., 2010), suggesting that extracellular, intramembrane, and intracellular interactions mediated by the core protein are also important in the biological functions of syndecans.
On the cell surface, syndecans function primarily as coreceptors that catalyze the encounter between ligands and their respective signaling receptors (Bernfield et al., 1999, Park et al., 2000b). Syndecans can also function as soluble HSPGs as their extracellular domain, replete with all their HS chains, can be proteolytically released from the cell surface by a process known as ectodomain shedding (Jalkanen et al., 1987, Bernfield et al., 1999, Hayashida et al., 2010). Syndecan shedding is thought to be an important post-translational mechanism that regulates syndecan functions as it both rapidly reduces the amount of cell surface HS and generates soluble syndecan ectodomains that can function as autocrine or paracrine effectors. Syndecan shedding is induced in vitro by several inflammatory factors (Fitzgerald et al., 2000, Park et al., 2004, Charnaux et al., 2005, Brule et al., 2006, Chung et al., 2006, Mahtouk et al., 2007, Yang et al., 2007) and in vivo under certain pathological conditions (Kainulainen et al., 1998, Kato et al., 1998, Park et al., 2001, Yang et al., 2002, Haynes et al., 2005, Xu et al., 2005, Hayashida et al., 2008a, Hayashida et al., 2009a, Hayashida et al., 2009b, Kliment et al., 2009, Hayashida et al., 2011, Haywood-Watson et al., 2011). The majority of syndecan shedding agonists induce shedding by activating outside-in signaling pathways (Fitzgerald et al., 2000, Park et al., 2000a, Park et al., 2004, Hayashida et al., 2008b), and several metalloproteinases can shed syndecan ectodomains (Li et al., 2002, Endo et al., 2003, Ding et al., 2005, Brule et al., 2006, Fears et al., 2006, Purushothaman et al., 2008, Pruessmeyer et al., 2010). These data suggest that the timing, location, and extent of syndecan shedding are regulated by a hierarchical mechanism involving shedding agonists, intracellular signaling pathways, and metalloproteinases.
Surprisingly, mice lacking syndecan-1 (Alexander et al., 2000, Park et al., 2001, Stepp et al., 2002) or syndecan-4 (Echtermeyer et al., 2001, Ishiguro et al., 2001) are healthy and fertile, and do not show major pathologies. However, dramatic pathological phenotypes emerge when both syndecan-1 null (Sdc1−/−) (Table 1) and Sdc4−/− (Echtermeyer et al., 2001, Ishiguro et al., 2001, Kon et al., 2008, Echtermeyer et al., 2009, Jiang et al., 2010, Ikesue et al., 2011) mice are challenged with disease-causing agents or conditions. These observations suggest that other syndecans or HSPGs can functionally compensate for the loss of syndecan-1 or -4 during development, but not in certain post-developmental processes, such as the pathogenesis of diseases. This review seeks to provide an overview of the key molecular functions of syndecan-1 in inflammatory diseases, cancer, and infection.
Section snippets
Inflammatory diseases
Inflammation is a fundamental host response to endogenous or exogenous agents that have the potential to cause tissue injury. The inflammatory response removes or sequesters harmful agents, and facilitates the restoration of the normal structure and function of damaged tissues. Multiple regulatory mechanisms have evolved to actively contain and resolve the inflammatory response in a timely manner to prevent excessive inflammatory tissue injury. However, when one or several of these mechanisms
Cancer
Syndecan-1 expression is dysregulated in many cancers, including carcinomas of the prostate (Kiviniemi et al., 2004), breast (Lendorf et al., 2011), pancreas (Juuti et al., 2005), ovary (Kusumoto et al., 2010), and colon (Hashimoto et al., 2008). Low syndecan-1 expression in tissue is associated with a worse prognosis in head and neck (Anttonen et al., 1999), lung (Anttonen et al., 2001) and colorectal (Lundin et al., 2005) cancers, whereas high levels of shed syndecan-1 in serum correlate with
Infectious diseases
Syndecan-1, as the major cell surface HSPG of epithelial cells, is thought to be targeted by microbial pathogens especially during the early phase of infection. Several studies suggest that syndecan-1 is subverted in several steps of infection, including the initial attachment and subsequent entry of pathogens into host cells, and inhibition of host defense mechanisms (Fig. 3). Evidence that these syndecan-1 functions are indeed important in the pathogenesis of infectious diseases is provided
Concluding remarks
Studies using animal models of diseases have provided clear indications that syndecan-1 plays an important role in the development of inflammatory diseases, cancer, and infection. Syndecan-1 is a critical cofactor in the pathogenesis of these diseases as Sdc1−/− mice only show dramatic pathological phenotypes when challenged with disease-causing agents or conditions, and do not show spontaneous pathologies. In general, syndecan-1 attenuates non-infectious inflammatory diseases by inhibiting
Acknowledgements
We thank our colleagues in the Park laboratory for helpful discussions. We apologize for not citing studies that may have been relevant but was omitted due to space limitations. Our research described in this review is supported by NIH Grants HL094613 and HL107472.
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