维生素连接蛋白
整合素
生物
细胞生物学
焦点粘着
细胞粘附
细胞迁移
癌症研究
细胞外基质
细胞
纤维连接蛋白
信号转导
生物化学
作者
Angara Sureshbabu,Hiroshi Okajima,Daisuke Yamanaka,Elizabeth Tonner,S. Shastri,Joanne Maycock,Małgorzata Szymanowska,John H. Shand,Shin‐Ichiro Takahashi,James Beattie,Grant Allan,D. J. Flint
摘要
Maintenance of tissue boundaries is crucial for control of metastasis. We describe a novel signalling pathway in which epithelial cell disruption can be minimised and thereby restricts epithelial-mesenchymal transgressions. This involves IGFBP-5 release from apoptotic cells, which increases epithelial cell adhesion on mesenchymal but not epithelial ECM and involves direct interaction of IGFBP-5 with α2β1 integrins. IGFBP-5 also induced adhesion to vitronectin in the absence of αVβ3 integrin, the vitronectin receptor, again via an α2β1 integrin-dependent action, suggesting that IGFBP-5 can induce spreading on matrices, even in the absence of the integrins normally used. Using IGFBP-5 mutants we demonstrate that the effect is IGF-independent but requires the heparin-binding domain in the c-terminus of IGFBP-5. A truncated c-terminal mutant of IGFBP-5 also induced adhesion. Adhesion induced by IGFBP-5 was cdc42-dependent and resulted in activation of ILK and Akt. Consistent with these changes, IGFBP-5 facilitated prolonged cell survival in nutrient-poor conditions and decreased phosphorylation of the stress-activated kinase p38MAPK. Whilst IGFBP-5 enhanced adhesion, it inhibited cell migration although this was not evident using the truncated c-terminal mutant, suggesting that effects of IGFBP-5 on adhesion and migration involve different mechanisms. These responses to IGFBP-5 would be anticipated to reduce metastatic potential.
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