title: Neuronal Thy-1 induces astrocyte adhesion by engaging syndecan-4 in a cooperative interaction with alphavbeta3 integrin that activates PKCalpha and RhoA.
abstract: Clustering of alphavbeta3 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 TNC(1) 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 PKCalpha implicated PKCalpha and RhoA activation in these events. Therefore, combined interaction of the astrocyte alphavbeta3-integrin-syndecan-4 receptor pair with Thy-1, promotes adhesion to the underlying matrix via PKCalpha- 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.
authors.affiliation: Laboratory of Cellular Communication, University of Chile, Santiago 8380453, Chile.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Avalos
authors.forename: Alejandra D
authors.initials: AD
authors.lastname: Valdivia
authors.forename: Nicolás
authors.initials: N
authors.lastname: Muñoz
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Herrera-Molina
authors.forename: Julio C
authors.initials: JC
authors.lastname: Tapia
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
authors.forename: Keith
authors.initials: K
authors.lastname: Burridge
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Andrew F G
authors.initials: AF
authors.lastname: Quest
authors.forename: Lisette
authors.initials: L
authors.lastname: Leyton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D016415:Sequence Alignment; D015398:Signal Transduction; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*; D018800:Thy-1 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D039302:Integrin alphaVbeta3; D053671:Syndecan-4; D018800:Thy-1 Antigens; D051571:Protein Kinase C-alpha; D020742:rhoA GTP-Binding Protein