Coregulation of Fibronectin Signaling and Matrix Contraction by Tenascin-C and Syndecan-4

Abstract

Syndecan-4 is a ubiquitously expressed heparan sulfate proteoglycan that modulates cell interactions with the extracellular matrix. It is transiently up-regulated during tissue repair by cells that mediate wound healing. Here, we report that syndecan-4 is essential for optimal fibroblast response to the three-dimensional fibrin-fibronectin provisional matrix that is deposited upon tissue injury. Interference with syndecan-4 function inhibits matrix contraction by preventing cell spreading, actin stress fiber formation, and activation of focal adhesion kinase and RhoA mediated-intracellular signaling pathways. Tenascin-C is an extracellular matrix protein that regulates cell response to fibronectin within the provisional matrix. Syndecan-4 is also required for tenascin-C action. Inhibition of syndecan-4 function suppresses tenascin-C activity and overexpression of syndecan-4 circumvents the effects of tenascin-C. In this way, tenascin-C and syndecan-4 work together to control fibroblast morphology and signaling and regulate events such as matrix contraction that are essential for efficient tissue repair. INTRODUCTIONTissue architecture is defined by the three-dimensional (3D) organization of the proteins and proteoglycans that comprise the extracellular matrix (ECM). Individual ECM components influence cell arrangements and activities through binding to transmembrane receptors, thus initiating intracellular signaling and altering gene expression and other downstream events. Tissues undergo continual maintenance and remodeling through controlled deposition and removal of specific ECM components. These changes in ECM composition and organization modulate cell behaviors and serve important roles throughout development and in the adult during both physiological and pathological processes (Lukashev and Werb, 1998).The provisional matrix that forms at sites of tissue injury undergoes extensive remodeling and turnover during wound repair. Composed predominantly of covalently cross-linked fibrin and plasma fibronectin (FN), this fibrin-FN provisional matrix coordinates the activities of cells involved in wound repair. It is remodeled over time to recapitulate normal tissue and this remodeling involves cellmediated contraction and deposition of new FN-rich matrix (Clark, 1996;Midwood et al., 2004). FN, a major component of the matrix, is a ubiquitously expressed, multifunctional extracellular glycoprotein that promotes cell adhesion. It controls many intracellular pathways and influences a wide range of cell functions (Hynes, 1990). For example, FN within a 3D fibrin-FN provisional matrix initiates signaling via focal adhesion kinase (FAK) and RhoA in order to promote fibroblast spreading, stress fiber formation, and focal adhesion assembly (Wenk et al., 2000;.The provisional matrix contacts many other ECM proteins that are induced at different stages of tissue repair, including thrombospondins, SPARC, and tenascin-C. These proteins are specifically up-regulated at wound sites where they modulate cell-ECM interactions (re...

Meet the Tenascins: Multifunctional and Mysterious

“…Almost all known binding sites lie in the fibronectin type III repeats or the fibrinogen globe, but evidence has been reported suggesting that the EGF-like repeats act as low affinity ligands for EGF receptors (15). As a consequence, cell interactions with tenascin-C are quite complex, and several signaling mechanisms have been identified, including recent observations that tenascin-C blocks focal adhesion kinase-and Rho-mediated signaling pathways activated by fibronectin (2,16,17) as well as stimulating Wnt and other growth-promoting pathways (18). For a detailed discussion of these mechanisms, please refer to Gertrude Orend's recent review (4).…”

The evolution of tenascins and fibronectin

“…13 Tenascin-C can also bind to fibronectin and prevent syndecan-4-fibronectin interactions, which in turn influences fibronectin signaling through integrins. 14,15,16 Tenascin-C knockout mice have profound behavioral abnormalities and other phenotypes that are primarily associated with aberrant stem cell migration, proliferation and differentiation. 1,11 Tenascin-R, the second tenascin to be discovered, is restricted in its expression to the nervous system 17 and tenascin-R knockout mice also display abnormal behavior.…”

Potential signaling pathway involved in sphingosine-1-phosphate-induced epithelial-mesenchymal transition in cancer

“…Excess focal adhesion formation is promoted by the overexpression of syndecan-4, resulting in a reduced level of cell migration (28). Additionally, syndecan-4-deficient mice and cells exhibit impaired wound repair and mesenchymal cell migration (29,30). Glypicans that are localized on the cell surface via a glycosylphosphatidylinositol moiety may regulate the cell responses to cell adhesion molecules and the ECM.…”