The dioxin receptor controls beta 1 integrin activation in fibroblasts through a Cbp-Csk-Src pathway

作者：Rey Barroso Javier; Colo Georgina P; Alvarez Barrientos Alberto; Redondo Munoz Javier; Carvajal Gonzalez Jose M; Mulero Navarro Sonia; Garcia Pardo Angeles; Teixido Joaquin; Fernandez Salguero Pedro M^*

来源：Cellular Signalling, 2013, 25(4): 848-859.

DOI：10.1016/j.cellsig.2013.01.010

• Cbp/Pag1/Src pathway
• AhR and beta 1 integrin activation
• Directional cell migration

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 beta 1 integrin activation and that this mechanism is AhR dependent. T-FGM AhR-/- fibroblasts displayed higher integrin in beta 1 activation, revealed by the increased binding of the activation reporter 9EG7 anti-beta 1 mAb and of a soluble fibronectin fragment, as well as by enhanced talin-beta 1 association. AhR-/- fibroblasts also showed increased fibronectin secretion and impaired directional migration. Notably, interfering Cbp expression in AhR-/- fibroblasts reduced beta 1 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-Tyr(416) activation and focal adhesion kinase (FAK) phosphorylation at the c-Src-responsive residues p-Tyr(576) and p-Tyr(577). The c-Src target and migration-related protein Cav1 was also hypophosphorylated at p-Tyr(14) in AhR -/- cells, and such effect was rescued by down-modulating Cbp levels. Thus, AhR regulates fibroblast migration by modulating beta 1 integrin activation via Cbp-dependent, Src-mediated signaling.

• 出版日期2013-4