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首页> 外文期刊>Molecular biology of the cell >Clustering of integrin alpha 5 at the lateral membrane restores epithelial polarity in invasive colorectal cancer cells
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Clustering of integrin alpha 5 at the lateral membrane restores epithelial polarity in invasive colorectal cancer cells

机译:在侧膜恢复侵袭性结肠直肠癌细胞中的整联蛋白α5的聚类恢复上皮极性

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摘要

Apicobasolateral polarity is a fundamental property of epithelial cells, and its loss is a hallmark of cancer. Integrin-mediated contact with the extracellular matrix defines the basal surface, setting in motion E-cadherin-mediated cell-cell contact, which establishes apicobasolateral polarity. Role(s) for lateral integrins in this polarization process and the consequences of their disruption are incompletely understood. We show that addition of an integrin beta 1-activating monoclonal antibody, P4G11, to invasive colorectal cancer cells in three-dimensional type 1 collagen reverts the invasive phenotype and restores apicobasolateral polarity. P4G11 induces clustering of integrin alpha 5 beta 1 at lateral, intercellular surfaces. This leads to deposition and polymerization of fibronectin and recruitment of paxillin to sites of lateral integrin alpha 5 beta 1 clustering and is followed by tight junction formation, as determined by ZO-1 localization. Inducible elimination of integrin alpha 5 abrogates the epithelial-organizing effects of P4G11. In addition, polymerization of fibronectin is required for the effects of P4G11, and addition of polymerized superfibronectin is sufficient to induce tight junction formation and apicobasolateral polarization. In the normal human colon, we show that integrin alpha 5 localizes to the lateral membrane of terminally differentiated colonocytes and that integrin alpha 5 staining may be reduced in colorectal cancer. Thus we propose a novel role for integrin alpha 5 beta 1 in regulating epithelial morphogenesis.
机译:亚偶像外侧极性是上皮细胞的基本性质,其损失是癌症的标志。整联蛋白介导的与细胞外基质接触定义了基础表面,在运动E-Cadherin介导的细胞 - 细胞接触中设置,该细胞 - 细胞接触,其建立了浮动外侧极性。这种偏振过程中侧联蛋白的作用以及其破坏的后果被不完全理解。我们表明,在三维1型胶原蛋白中添加了整合蛋白β1-活化单克隆抗体,P4G11,以侵入式结直肠癌细胞再转移侵入性表型并恢复暂性缺卵性极性。 P4G11在侧面,细胞表面下诱导整联蛋白α5β1的聚类。这导致纤连蛋白的沉积和聚合,并募集卵毛蛋白至横向整联蛋白α5β1聚类的位置,然后通过ZO-1定位测定的紧密结形成。诱导消除整联蛋白α5废除了P4G11的上皮组织效果。此外,P4G11的效果需要纤连蛋白的聚合,并加入聚合的超纤维素蛋白足以诱导紧密的接线形成和浮动外侧极化。在正常人结肠中,我们表明整合蛋白α5定位于终端分化的结肠细胞的横向膜,并且整合素α5染色可以在结肠直肠癌中降低。因此,我们为整合蛋白α5β1调节上皮形态发生时提出了一种新的作用。

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