The Dioxin receptor modulates Caveolin-1 mobilization during directional migration: role of cholesterol

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.

Author: Javier Rey-BarrosoAlberto Alvarez-BarrientosEva Rico-LeoMarÃƒÂa Contador-TrocaJosÃƒÂ© M Carvajal-GonzalezAsier EcharriMiguel A del PozoPedro M Fernandez-Salguero
Credits/Source: Cell Communication and Signaling 2014, 12:57

Published on: 2014-09-21

News Provider: 7thSpace Interactive / EUPB Press Office

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