title: 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-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 β1 integrin activation via Cbp-dependent, Src-mediated signaling.
authors: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain.
authors: Javier
authors: J
authors: Rey-Barroso
authors: Georgina P
authors: GP
authors: Colo
authors: Alberto
authors: A
authors: Alvarez-Barrientos
authors: Javier
authors: J
authors: Redondo-Muñoz
authors: José M
authors: JM
authors: Carvajal-González
authors: Sonia
authors: S
authors: Mulero-Navarro
authors: Angeles
authors: A
authors: García-Pardo
authors: Joaquín
authors: J
authors: Teixidó
authors: Pedro M
authors: PM
authors: Fernandez-Salguero
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D051242:Caveolin 1 / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D051242:Caveolin 1; D005353:Fibronectins; D019012:Integrin beta1; D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D012795:Sialoglycoproteins; D000081247:CSK Tyrosine-Protein Kinase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases