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

Abstract: 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. [Copyright &y& Elsevier]