Neuronal Thy-1 induces astrocyte adhesion by engaging syndecan-4 in a cooperative interaction with alphavbeta3 integrin that activates PKCalpha and RhoA.
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.
Avalos
Ana María
AM
Laboratory of Cellular Communication, University of Chile, Santiago 8380453, Chile.
Valdivia
Alejandra D
AD
Muñoz
Nicolás
N
Herrera-Molina
Rodrigo
R
Tapia
Julio C
JC
Lavandero
Sergio
S
Chiong
Mario
M
Burridge
Keith
K
Schneider
Pascal
P
Quest
Andrew F G
AF
Leyton
Lisette
L
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*
D039302:Integrin alphaVbeta3; D053671:Syndecan-4; D018800:Thy-1 Antigens; D051571:Protein Kinase C-alpha; D020742:rhoA GTP-Binding Protein