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The Dioxin Receptor Regulates the Constitutive Expression of the Vav3 Proto-Oncogene and Modulates Cell Shape and Adhesion

AuthorsCarvajal-González, José M.; Sauzeau, Vincent; Bustelo, Xosé R.
Issue Date2009
PublisherAmerican Society for Cell Biology
CitationMolecular Biology of the Cell 20(6): 1715-1727 (2009)
AbstractThe dioxin receptor (AhR) modulates cell plasticity and migration, although the signaling involved remains unknown. Here, we report a mechanism that integrates AhR into these cytoskeleton-related functions. Immortalized and mouse embryonic fibroblasts lacking AhR (AhR-/-) had increased cell area due to spread cytoplasms that reverted to wild-type morphology upon AhR re-expression. The AhR-null phenotype included increased F-actin stress fibers, depolarized focal adhesions, and enhanced spreading and adhesion. The cytoskeleton alterations of AhR- /- cells were due to down-regulation of constitutive Vav3 expression, a guanosine diphosphate/guanosine triphosphate exchange factor for Rho/Rac GTPases and a novel transcriptional target of AhR. AhR was recruited to the vav3 promoter and maintained constitutive mRNA expression in a ligand-independent manner. Consistently, AhR-/- fibroblasts had reduced Racl activity and increased activation of the RhoA/Rho kinase (Rock) pathway. Pharmacological inhibition of Racl shifted AhR+/+ fibroblasts to the null phenotype, whereas Rock inhibition changed AhR-null cells to the AhR+/+ morphology. Knock-down of vav3 transcripts by small interfering RNA induced cytoskeleton defects and changes in adhesion and spreading mimicking those of AhR-null cells. Moreover, vav3-/- MEFs, as AhR-/- mouse embryonic fibroblasts, had increased cell area and enhanced stress fibers. By modulating Vav3-dependent signaling, AhR could regulate cell shape, adhesion, and migration under physiological conditions and, perhaps, in certain pathological states. © 2009 by The American Society for Cell Biology.
Description13 páginas, 12 figuras.-- et al.
Publisher version (URL)http://dx.doi.org/10.1091/mbc.E08-05-0451
Identifiersdoi: 10.1091/mbc.E08-05-0451
issn: 1059-1524
e-issn: 1939-4586
Appears in Collections:(IBMCC) Artículos
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