title: Thy-1-mediated cell-cell contact induces astrocyte migration through the engagement of αVβ3 integrin and syndecan-4.
abstract: Cell adhesion to the extracellular matrix proteins occurs through interactions with integrins that bind to Arg-Gly-Asp (RGD) tripeptides, and syndecan-4, which recognizes the heparin-binding domain of other proteins. Both receptors trigger signaling pathways, including those that activate RhoGTPases such as RhoA and Rac1. This sequence of events modulates cell adhesion to the ECM and cell migration. Using a neuron-astrocyte model, we have reported that the neuronal protein Thy-1 engages αVβ3 integrin and syndecan-4 to induce RhoA activation and strong astrocyte adhesion to their underlying substrate. Thus, because cell-cell interactions and strong cell attachment to the matrix are considered antagonistic to cell migration, we hypothesized that Thy-1 stimulation of astrocytes should preclude cell migration. Here, we studied the effect of Thy-1 expressing neurons on astrocyte polarization and migration using a wound-healing assay and immunofluorescence analysis. Signaling molecules involved were studied by affinity precipitation, western blotting and the usage of specific antibodies. Intriguingly, Thy-1 interaction with its two receptors was found to increase astrocyte polarization and migration. The latter events required interactions of these receptors with both the RGD-like sequence and the heparin-binding domain of Thy-1. Additionally, prolonged Thy-1-receptor interactions inhibited RhoA activation while activating FAK, PI3K and Rac1. Therefore, sustained engagement of integrin and syndecan-4 with the neuronal surface protein Thy-1 induces astrocyte migration. Interestingly we identify here, a cell-cell interaction that despite initially inducing strong cell attachment, favors cell migration upon persistent stimulation by engaging the same signaling receptors and molecules as those utilized by the extracellular matrix proteins to stimulate cell movement.
authors.affiliation: Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile.
authors.forename: Milene
authors.initials: M
authors.lastname: Kong
authors.forename: Nicolás
authors.initials: N
authors.lastname: Muñoz
authors.forename: Alejandra
authors.initials: A
authors.lastname: Valdivia
authors.forename: Alvaro
authors.initials: A
authors.lastname: Alvarez
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Herrera-Molina
authors.forename: Areli
authors.initials: A
authors.lastname: Cárdenas
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Keith
authors.initials: K
authors.lastname: Burridge
authors.forename: Andrew F G
authors.initials: AF
authors.lastname: Quest
authors.forename: Lisette
authors.initials: L
authors.lastname: Leyton
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D002450:Cell Communication; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity; D049109:Cell Proliferation; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D053671:Syndecan-4 / Q000378:metabolism*; D018800:Thy-1 Antigens / Q000378:metabolism*; D014945:Wound Healing; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D053671:Syndecan-4; D018800:Thy-1 Antigens; C047981:arginyl-glycyl-aspartic acid; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein