The dioxin receptor controls β1 integrin activation in fibroblasts through a Cbp–Csk–Src pathway

• Published in: Cellular signalling 2013-04, Vol.25 (4), p.848-859
• Main Authors: Rey-Barroso, Javier, Colo, Georgina P., Alvarez-Barrientos, Alberto, Redondo-Muñoz, Javier, Carvajal-González, José M., Mulero-Navarro, Sonia, García-Pardo, Angeles, Teixidó, Joaquín, Fernandez-Salguero, Pedro M.
• Format: Article
• Language: English
• Subjects: Actins - metabolism; AhR and β1 integrin activation; Animals; Caveolin 1 - metabolism; Cbp/Pag1/Src pathway; Cell Adhesion; Cell Movement; Directional cell migration; Fibroblasts - metabolism; Fibroblasts - secretion; Fibronectins - metabolism; Fibronectins - secretion; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Integrin beta1 - metabolism; Membrane Proteins - metabolism; Mice; Phosphoproteins - metabolism; Phosphorylation; Receptors, Aryl Hydrocarbon - antagonists & inhibitors; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Sialoglycoproteins - metabolism; Signal Transduction; src-Family Kinases - metabolism
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2013.01.010

Recent studies have suggested a regulatory role for the dioxin receptor (AhR) in cell adhesion and migration. Following our previous work, we report here that the C-terminal Src kinase-binding protein (Cbp) signaling pathway controls β1 integrin activation and that this mechanism is AhR dependent. T-FGM AhR−/− fibroblasts displayed higher integrin β1 activation, revealed by the increased binding of the activation reporter 9EG7 anti-β1 mAb and of a soluble fibronectin fragment, as well as by enhanced talin-β1 association. AhR−/− fibroblasts also showed increased fibronectin secretion and impaired directional migration. Notably, interfering Cbp expression in AhR−/− fibroblasts reduced β1 integrin activation, improved cell migration and rescued wild-type cell morphology. Cbp over-expression in T-FGM AhR−/− cells enhanced the formation of inhibitory Csk–Cbp complexes which in turn reduced c-Src p-Tyr416 activation and focal adhesion kinase (FAK) phosphorylation at the c-Src-responsive residues p-Tyr576 and p-Tyr577. The c-Src target and migration-related protein Cav1 was also hypophosphorylated at p-Tyr14 in AhR−/− cells, and such effect was rescued by down-modulating Cbp levels. Thus, AhR regulates fibroblast migration by modulating β1 integrin activation via Cbp-dependent, Src-mediated signaling. ► A novel mechanism for the control of cell adhesion and migration by AhR is proposed. ► AhR modulates β1 integrin activation by inside-out control of the Cbp/Csk–Src pathway. ► AhR also regulates β1 integrin activation by outside-in signaling from fibronectin. ► AhR expression should be considered in pathologies involving β1 integrin activation.