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First published online 1 September 2009
doi: 10.1242/jcs.034827

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Neuronal Thy-1 induces astrocyte adhesion by engaging syndecan-4 in a cooperative interaction with vβ3 integrin that activates PKC and RhoA

Ana María Avalos^1,2,3,*, Alejandra D. Valdivia^1,2,3,*, Nicolás Muñoz^1,2,3, Rodrigo Herrera-Molina^1,2,3, Julio C. Tapia^2,3, Sergio Lavandero^2,3,4, Mario Chiong^2,4, Keith Burridge⁵, Pascal Schneider⁶, Andrew F. G. Quest^1,2,3 and Lisette Leyton^1,2,3,

¹ Laboratory of Cellular Communication, University of Chile, Santiago 8380453, Chile
² FONDAP Center for Molecular Studies of the Cell (CEMC), University of Chile, Santiago 8380453, Chile
³ Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago 8380453, Chile
⁴ Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago 8380453, Chile
⁵ Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
⁶ Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

Author for correspondence (lleyton{at}med.uchile.cl)

Accepted 6 July 2009

Clustering of vβ3 integrin after interaction with the RGD-like integrin-binding sequence present in neuronal Thy-1 triggers formation of focal adhesions and stress fibers in astrocytes via RhoA activation. A putative heparin-binding domain is present in Thy-1, raising the possibility that this membrane protein stimulates astrocyte adhesion via engagement of an integrin and the proteoglycan syndecan-4. Indeed, heparin, heparitinase treatment and mutation of the Thy-1 heparin-binding site each inhibited Thy-1-induced RhoA activation, as well as formation of focal adhesions and stress fibers in DI TNC₁ astrocytes. These responses required both syndecan-4 binding and signaling, as evidenced by silencing syndecan-4 expression and by overexpressing a syndecan-4 mutant lacking the intracellular domain, respectively. Furthermore, lack of RhoA activation and astrocyte responses in the presence of a PKC inhibitor or a dominant-negative form of PKC implicated PKC and RhoA activation in these events. Therefore, combined interaction of the astrocyte vβ3-integrin–syndecan-4 receptor pair with Thy-1, promotes adhesion to the underlying matrix via PKC- and RhoA-dependent pathways. Importantly, signaling events triggered by such receptor cooperation are shown here to be the consequence of cell-cell rather than cell-matrix interactions. These observations are likely to be of widespread biological relevance because Thy-1–integrin binding is reportedly relevant to melanoma invasion, monocyte transmigration through endothelial cells and host defense mechanisms.

Key words: Thy-1, Syndecan-4, Cell adhesion, Astrocytes

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