title: The Dioxin receptor modulates Caveolin-1 mobilization during directional migration: role of cholesterol.
abstract: BACKGROUND
  Adhesion and migration are relevant physiological functions that must be regulated by the cell under both normal and pathological conditions. The dioxin receptor (AhR) has emerged as a transcription factor regulating both processes in mesenchymal, epithelial and endothelial cells. Indirect results suggest that AhR could cooperate not only with additional transcription factors but also with membrane-associated proteins to drive such processes.
  
  
  RESULTS
  In this study, we have used immortalized and primary dermal fibroblasts from wild type (AhR+/+) and AhR-null (AhR-/-) mice to show that AhR modulates membrane distribution and mobilization of caveolin-1 (Cav-1) during directional cell migration. AhR co-immunoprecipitated with Cav-1 and a fraction of both proteins co-localized to detergent-resistant membrane microdomains (DRM). Consistent with a role of AhR in the process, AhR-/- cells had a significant reduction in Cav-1 in DRMs. Moreover, high cell density reduced AhR nuclear levels and moved Cav-1 from DRMs to the soluble membrane in AhR+/+ but not in AhR-/- cells. Tyrosine-14 phosphorylation had a complex role in the mechanism since its upregulation reduced Cav-1 in DRMs in both AhR+/+ and AhR-/-cells, despite the lower basal levels of Y14-Cav-1 in the null cells. Fluorescence recovery after photobleaching revealed that AhR knock-down blocked Cav-1 transport to the plasma membrane, a deficit possibly influencing its depleted levels in DRMs. Membrane distribution of Cav-1 in AhR-null fibroblasts correlated with higher levels of cholesterol and with disrupted membrane microdomains, whereas addition of exogenous cholesterol changed the Cav-1 distribution of AhR+/+ cells to the null phenotype. Consistently, higher cholesterol levels enhanced caveolae-dependent endocytosis in AhR-null cells.
  
  
  CONCLUSIONS
  These results suggest that AhR modulates Cav-1 distribution in migrating cells through the control of cholesterol-enriched membrane microdomains. Our study also supports the likely possibility of membrane-related, transcription factor independent, functions of AhR.
authors.forename: Javier
authors.initials: J
authors.lastname: Rey-Barroso
authors.forename: Alberto
authors.initials: A
authors.lastname: Alvarez-Barrientos
authors.forename: Eva
authors.initials: E
authors.lastname: Rico-Leo
authors.forename: María
authors.initials: M
authors.lastname: Contador-Troca
authors.forename: José M
authors.initials: JM
authors.lastname: Carvajal-Gonzalez
authors.forename: Asier
authors.initials: A
authors.lastname: Echarri
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Del Pozo
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Fernandez-Salguero
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004705:Endocytosis; D005347:Fibroblasts / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D018336:Receptors, Aryl Hydrocarbon; D002784:Cholesterol