Syndecan-4 Clustering Induces Cell Migration in a PDZ-Dependent Manner

Abstract

Abstract-Cell migration is a dynamic process involving formation of a leading edge in the direction of migration and adhesion points from which tension is generated to move the cell body forward. At the same time, disassembly of adhesion points occurs at the back of the cell, a region known as the trailing edge. Syndecan-4 (S4) is a transmembrane proteoglycan thought to be involved in the formation of focal adhesions. Recent studies have shown that its cytoplasmic domain can engage in signal transduction, making S4 a bona fide receptor. Here, we show that ligand clustering of cell surface S4 on endothelial cells initiates a signaling cascade that results in activation of Rac1, induction of cell polarization, and stimulation of cell migration that depends on S4 interaction with its PDZ-binding partner. Expression of an S4 mutant lacking its PDZ-binding region (S4-PDZ Ϫ ) leads to decreased cell motility and a failure to form a trailing edge. On clustering S4, but not S4-PDZ Ϫ , targets activated Rac1 to the leading edge of live cells. Cells lacking synectin, a PDZ domain containing protein that interacts with S4, fail to migrate in response to S4 clustering. Both S4-PDZ Ϫ -expressing and synectin Ϫ/Ϫ endothelial cells exhibit elevated basal levels of Rac1. Thus, our data suggest that S4 promotes endothelial cell migration in response to ligand binding by activating Rac1 and localizing it to the leading edge, and that these processes are dependent on its PDZ-binding domain interaction with synectin. (Circ Res. 2006;98:1398-1404.)Key Words: syndecan Ⅲ synectin Ⅲ migration Ⅲ endothelial cells Ⅲ Rac1 Ⅲ PDZ S yndecans are a family of four transmembrane proteoglycans containing both heparan sulfate and chondroitin sulfate chains. Different family members are expressed in various cell types, with syndecan-4 (S4) demonstrating nearly ubiquitous expression. Syndecans have been thought to act as coreceptors for various heparin-binding growth factors such as fibroblast growth factors (FGFs), vascular endothelial growth factors, and fibronectin-binding integrins. [1][2][3][4] However, recent studies have suggested that the intracellular domains of syndecans, and in particular, the S4 intracellular domain, can directly engage in signal transduction. [5][6][7][8][9] The cytoplasmic tail of the syndecans contains two highly conserved domains. The first (C1) is the membrane-proximal region that binds tubulin, Src kinase, ezrin, and cortactin. 3 The second (C2) is a C-terminal region that contains a PDZ-domain binding motif. The part of the molecule between the two conserved domains has been termed the variable domain, and its sequence is unique to each syndecan family member. The variable domain of S4 binds to the phosphatidyl inositol 4,5,bisphosphate/protein kinase C␣ (PKC␣) complex, ␣-actinin, and syndesmos. 3 These interactions are responsible for the previously demonstrated S4 role in cytoskeleton regulation that includes formation of focal adhesions, of dynamic stress fibers, and of cell protrusions. 9 -15 S4 is an acut...

Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia

“…Syndecan 4 is also expressed by endothelial cells wherein it regulates multiple aspects of angiogenesis including ligand endocytosis (e.g., FGF-2 and VEGF) and stimulates endothelial migration and tubularization (Tkachenko et al, 2004(Tkachenko et al, , 2006Nunes et al, 2008). This raises the possibility that motoneuron-derived angiogenin may stimulate endothelial cells to induce neovascularization.…”

Epac increases melanoma cell migration by a heparan sulfate-related mechanism

“…Syndecan is known to regulate cell migration in various cancer cells through its binding to extracellular HS (19). Syndecan-translocation to lipid rafts plays a role in cell migration (39). Lipid rafts are known to serve as platforms for molecules (42), and translocation of molecules, such as ICAM-1 (30), calpain (32), and integrins (25), to lipid rafts is necessary to activate cell migration.…”

“…On the other hand, studies have demonstrated that the clustering of syndecan in lipid rafts/caveolae is necessary for enhancing cell migration (13). To examine involvement of syndecan-2 clustering in Epac-induced cell migration, further experiments, such as those using overexpression of recombinant syndecan-2 lacking PDZ domain, which mediates syndecan clustering (39), is required. In addition, recent reports have demonstrated that syndecans increases cell migration via integrin ␣2 (10), laminin ␣3 (1), focal adhesion formation, and protein kinase C (10).…”

Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling

“…They also have higher mortality after LPS injection (7) and exhibit defective muscle repair and myofiber organization as a result of inefficient differentiation and migration of muscle satellite cells (8). We and others have also demonstrated that S4 plays a critical role in the control of cell polarity, by controlling Rho GTPase activity (9)(10)(11), as well as in planar cell polarity (12). S4 has also been recently identified as a putative mechanosensor (13).…”