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

Cell Communication and Signaling

Research

Miguel A del Pozo¹  Asier Echarri¹  Eva Rico-Leo²  María Contador-Troca²  Pedro M Fernandez-Salguero²  Javier Rey-Barroso²  José M Carvajal-Gonzalez³  Alberto Alvarez-Barrientos⁴ 

[1] Departamento de Biología Vascular e Inflamación,, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029, Madrid, Spain;Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias,, Universidad de Extremadura, 06071, Badajoz, Spain;Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, 10029, New York, USA;Servicio de Técnicas Aplicadas a las Biociencia, Universidad de Extremadura, 06071, Badajoz, Spain;

关键词: Dioxin receptor;    Caveolin-1;    Membrane microdomains;    Endocytosis;    Cholesterol;   

DOI  :  10.1186/s12964-014-0057-7

 received in 2014-04-05, accepted in 2014-09-05,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundAdhesion 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.ResultsIn 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.ConclusionsThese 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.

【 授权许可】

Unknown   
© Rey-Barroso et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.