Protein kinase C-dependent mobilization of the alpha6beta4 integrin from hemidesmosomes and its association with actin-rich cell protrusions drive the chemotactic migration of carcinoma cells.
Protein kinase C-dependent mobilization of the alpha6beta4 integrin from hemidesmosomes and its association with actin-rich cell protrusions drive the chemotactic migration of carcinoma cells.
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DOI：
10.1083/jcb.146.5.1147
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发表时间：
1999-09-06
期刊：
影响因子：
--
通讯作者：
Mercurio AM
中科院分区：
文献类型：
--
作者：
Rabinovitz I;Toker A;Mercurio AM
我们探讨了这样的假设，即组装半桥粒的癌细胞的趋化性迁移涉及信号通路的激活，该信号通路从这些稳定的粘附复合物中释放α6β4整联蛋白，并促进其与细胞突起中的F-肌动蛋白的结合，使其能够在迁移中发挥作用。使用鳞状细胞癌衍生的A431细胞，因为它们表达α6β4并响应EGF刺激而迁移。使用功能阻断抗体，我们发现α6β4整合素参与EGF刺激的趋化性，并且是层粘连蛋白-1上层粘连蛋白形成所必需的。在刺激A431趋化性的EGF浓度下（约1 ng/ml），α6β4整联蛋白从半桥粒中被动员，如通过间接免疫荧光显微镜使用该整联蛋白和半桥粒组分的特异性mAb以及其从去污剂提取获得的细胞角蛋白部分中的损失所证明的。EGF刺激还增加了含有α6β4和F-肌动蛋白的片状伪足和膜皱褶的形成。重要的是，我们证明了α6β4从半桥粒的动员及其重新分配到细胞突起的机制涉及蛋白激酶C-α的激活，并且它与β4整联蛋白亚基在丝氨酸残基上的磷酸化有关。因此，A431细胞在层粘连蛋白-1上的趋化性迁移不仅需要形成富含F-肌动蛋白的细胞突起（介导α6β4依赖性细胞运动），还需要蛋白激酶C破坏含α6β4的半桥粒。
We explored the hypothesis that the chemotactic migration of carcinoma cells that assemble hemidesmosomes involves the activation of a signaling pathway that releases the α6β4 integrin from these stable adhesion complexes and promotes its association with F-actin in cell protrusions enabling it to function in migration. Squamous carcinoma-derived A431 cells were used because they express α6β4 and migrate in response to EGF stimulation. Using function-blocking antibodies, we show that the α6β4 integrin participates in EGF-stimulated chemotaxis and is required for lamellae formation on laminin-1. At concentrations of EGF that stimulate A431 chemotaxis (∼1 ng/ml), the α6β4 integrin is mobilized from hemidesmosomes as evidenced by indirect immunofluorescence microscopy using mAbs specific for this integrin and hemidesmosomal components and its loss from a cytokeratin fraction obtained by detergent extraction. EGF stimulation also increased the formation of lamellipodia and membrane ruffles that contained α6β4 in association with F-actin. Importantly, we demonstrate that this mobilization of α6β4 from hemidesmosomes and its redistribution to cell protrusions occurs by a mechanism that involves activation of protein kinase C-α and that it is associated with the phosphorylation of the β4 integrin subunit on serine residues. Thus, the chemotactic migration of A431 cells on laminin-1 requires not only the formation of F-actin–rich cell protrusions that mediate α6β4-dependent cell movement but also the disruption of α6β4-containing hemidesmosomes by protein kinase C.
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影响因子：
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作者：
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影响因子：
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