期刊
CELLULAR SIGNALLING
卷 25, 期 4, 页码 848-859出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2013.01.010
关键词
Cbp/Pag1/Src pathway; AhR and beta 1 integrin activation; Directional cell migration
类别
资金
- Spanish Ministry of Science and Innovation [SAF2008-00462, BFU2011-22678, SAF2008-00479, SAF2011-24022, SAF-2009-07035]
- Junta de Extremadura [GR10008]
- Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Fondo de Investigaciones Sanitarias (FIS), Carlos III Institute, Spanish Ministry of Health [RD06/0020/1016, RD06/0020/0011]
- European Union FEDER program
- Servicio de Tecnicas Aplicadas a la Biociencia, Universidad de Extremadura
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. (C) 2013 Elsevier Inc. All rights reserved.
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