A Shared Mechanism of Adhesion Modulation for Tenascin-C and Fibulin-1

Abstract

Adhesion modulatory proteins are important effectors of cell-matrix interactions during tissue remodeling and regeneration. They comprise a diverse group of matricellular proteins that confer antiadhesive properties to the extracellular matrix (ECM). We compared the inhibitory effects of two adhesion modulatory proteins, fibulin-1 and tenascin-C, both of which bind to the C-terminal heparin-binding (HepII) domain of fibronectin (FN) but are structurally distinct. Here, we report that, like tenascin-C, fibulin-1 inhibits fibroblast spreading and cell-mediated contraction of a fibrin-FN matrix. These proteins act by modulation of focal adhesion kinase and extracellular signal-regulated kinase signaling. The inhibitory effects were bypassed by lysophosphatidic acid, an activator of RhoA GTPase. Fibroblast response to fibulin-1, similar to tenascin-C, was dependent on expression of the heparan sulfate proteoglycan syndecan-4, which also binds to the HepII domain. Therefore, blockade of HepII-mediated signaling by competitive binding of fibulin-1 or tenascin-C represents a shared mechanism of adhesion modulation among disparate modulatory proteins. INTRODUCTIONTissue architecture is determined by positioning of cells within the fibrillar assemblage of proteins, proteoglycans, and other components that comprise the extracellular matrix (ECM). Organization and composition of the ECM have significant impacts on many cellular functions. By binding to transmembrane receptors, individual ECM components affect cell arrangements and initiate signaling events that alter gene expression and regulate cell communication. Fibronectin (FN) is a ubiquitously expressed, multifunctional ECM glycoprotein that promotes cell adhesion and plays important roles in tissue development, repair, and remodeling (Hynes, 1990). Cell interactions with FN are largely dependent on integrin receptors with subsequent engagement of intracellular signaling and cytoskeletal components (Hynes, 2002). Tissue development and remodeling require changes in cell adhesion to allow cell proliferation, cell motility, and ECM reorganization (Singer and Clark, 1999). Modulation of cell adhesion can be achieved by modifications in FN matrix organization or composition (Sechler et al., 1998;Midwood et al., 2006) or by the deposition of adhesion modulatory or matricellular proteins (Bornstein and Sage, 2002), including tenascin-C, fibulin-1, thrombospondin-1 (TSP-1), and many others (Fassler et al., 1996;Bornstein, 2001;Chiquet-Ehrismann and Chiquet, 2003;Midwood et al., 2004b).Expression of proteins that modulate cell adhesion causes reduced cell interactions with adhesive ECM, thus allowing cell movement, shape changes, proliferation, and other related processes (Chiquet-Ehrismann, 1991;Orend and Chiquet-Ehrismann, 2000). The suppression of adhesion-related signal transduction produces dramatic changes in cytoskeletal organization and in the kinetics of cell contact with the ECM. Adhesion modulatory proteins comprise an increasingly diverse group, suggesting that t...

Syndecans as receptors and organizers of the extracellular matrix

“…Consistent with its distribution at the edges of the wounds, tenascin-C may promote migration rather than premature contraction (Midwood et al 2004). A similar mechanism of adhesion modulation has been proposed for the unrelated protein, fibulin-1, suggesting that this may be a common mechanism to fine-tune adhesion (Williams and Schwarzbauer 2009). Other research, again in fibroblasts, has shown that the blocking of fibronectin-syndecan-4 interaction by tenascin-C inhibits cell anchorage on fibronectin, leading to the blockage of cell cycle progression but the stimulation of tumour cell proliferation (Orend et al 2003;, Huang et al 2001).…”

Tenascin-C deficiency attenuates TGF-β-mediated fibrosis following murine lung injury

“…N ϭ 5 for each condition; *P Ͻ 0.05. Third, TNC is known to restrain RhoA-mediated activation of the extracellular regulated kinase (Erk) pathway in fibroblasts (49), and it has recently been shown that Erk signaling opposes Smad-dependent TGF-␤ signaling in lung epithelial cell lines, potentially regulating both epithelial-mesenchymal and mesenchymal-epithelial transitions (39). While speculative, it is possible that the absence of TNC after ALI leads to excessive Erk signaling which may in turn reduce Smad-3 through effects on transcription and proteasomal activity by as yet undescribed mechanisms.…”

Temporospatial expression of fibulin-1 after acute spinal cord injury in rats

“…Furthermore, research by Selwyn et al showed that fibulin-1 can alter ECM-mediated cell signaling through inhibiting ERK activation. 35 Collectively, these findings provide evidence that fibulin-1 plays a crucial role in neuronal apoptosis after SCI by blocking ERK signaling pathways in neurons. Consideration of other known ligands of fibulin-1 leads us to propose that fibulin-1-mediated apoptosis may also occur through additional signaling pathways.…”