Ligation of the β4 integrin triggers adhesion behavior of human keratinocytes by an "inside-out" mechanism
Ligation of the β4 integrin triggers adhesion behavior of human keratinocytes by an "inside-out" mechanism
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DOI：
10.1111/j.0022-202x.2004.23323.x
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发表时间：
2004-09-01
影响因子：
6.5
通讯作者：
Bernd, A
中科院分区：
文献类型：
--
作者：
Kippenberger, S;Loitsch, S;Bernd, A
癌变被认为是一个涉及半桥粒组织功能变化的多步骤过程。在正常皮肤角质形成细胞中，α（6）β（4）整联蛋白的表达限于增殖基底层，并介导与下面的基底膜的稳定粘附。在癌细胞中的观察显示α（6）β（4）整联蛋白从半桥粒复合物的功能和空间解离，其刺激细胞迁移，因此可能有助于癌侵袭。我们现在已经评估了上皮细胞在不同转化阶段对β 4整合素激活的反应的粘附行为。研究表明，β（4）整合素的连接增强了癌细胞和癌前细胞对未修饰塑料的粘附。相反，正常人角质形成细胞的粘附行为不受β（4）整联蛋白连接的影响。为了解释β（4）介导的粘附的机制，测试了整合素的“由内而外”活化的假设。有证据表明，对于表达α（6）β（4）整联蛋白的细胞，β（4）整联蛋白的连接增加β（1）整联蛋白介导的粘附。此外，β（4）整联蛋白的连接导致PKB/Akt在两个磷酸化位点的磷酸化。通过显性负性过表达功能性阻断PKB/Akt可降低对β 4整合素连接反应的细胞粘附。总之，本数据建立了β（4）整联蛋白的连接和β（1）整联蛋白介导的癌细胞和癌前细胞中的细胞粘附之间的联系。因此，这些发现提供了对癌发生过程中转化过程的进一步了解，并显示β（4）整合素是细胞粘附的关键调节因子。
Carcinogenesis is considered as a multistep process involving functional changes in the hemidesmosomal organization. In normal skin keratinocytes, expression of the alpha(6)beta(4) integrin is restricted to the proliferative basal layer and mediates stable adhesion to the underlying basement membrane. Observations in carcinoma cells show a functional and spatial dissociation of the alpha(6)beta(4) integrin from the hemidesmosomal complex, which stimulates cell migration and, therefore, may contribute to carcinoma invasion. We now have evaluated the adhesion behavior of epithelial cells at different stages of transformation in response to activation of the beta(4) integrin. It is demonstrated that ligation of the beta(4) integrin augmented adhesion of carcinoma and pre-carcinoma cells to non-modified plastic. In contrast, adhesion behavior of normal human keratinocytes was not influenced by ligation of the beta(4) integrin. In order to explain the mechanism of beta(4)-mediated adhesion, the hypothesis of an "inside-out" activation of integrins was tested. Evidence is given that for cells expressing the alpha(6)beta(4) integrin, ligation of the beta(4) integrin increased beta(1) integrin-mediated adhesion. Furthermore, ligation of the beta(4) integrin led to phosphorylation of PKB/Akt at both phosphorylation sites. Functional blocking of PKB/Akt by dominant-negative overexpression decreased cell adhesion in response to beta(4) integrin ligation. Taken together, the present data establish a link between the ligation of the beta(4) integrin and beta(1) integrin-mediated cell adhesion in carcinoma and pre-carcinoma cells. Hence, these findings provide further insight into the conversion processes during carcinogenesis and show the beta(4) integrin to be a key regulator of cellular adhesion.