Fascin Rigidity and L-plastin Flexibility Cooperate in Cancer Cell Invadopodia and Filopodia*
Fascin Rigidity and L-plastin Flexibility Cooperate in Cancer Cell Invadopodia and Filopodia*
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DOI：
10.1074/jbc.m115.706937
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
Isabel Van Audenhove;M. Denert;Ciska Boucherie;Leen Pieters;M. Cornelissen;J. Gettemans
中科院分区：
文献类型：
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作者：
Isabel Van Audenhove;M. Denert;Ciska Boucherie;Leen Pieters;M. Cornelissen;J. Gettemans
内陷和丝状足是动态的、基于肌动蛋白的突起，有助于癌细胞的迁移、侵袭和转移。肌动蛋白束的力量对于它们的突起活动是必不可少的。已知的是，捆绑蛋白Fascin在侵袭足纲和丝状足纲中都起作用。随着人们越来越多地认识到与功能相关的蛋白质之间的相互作用，不太可能只有束蛋白才能在这些突起中结合肌动蛋白。另一个有趣的候选者是L-纤溶酶，它通常在造血细胞中表达，但被认为是许多癌症类型的共同标记物。我们鉴定了L-纤溶酶是一种新的侵袭性成分，在那里它有助于降解和侵袭。通过特定的、高亲和力的纳米体抑制法菌素或L-纤溶酶的捆绑，我们进一步揭示了它们之间的协同作用模式。我们发现，由于显著不同的捆绑特征，捆绑器不能相互补偿：L-血浆蛋白束要薄得多，包装也不那么紧密。复合束采用中间表型，筋膜提供突出力和结构稳定性所需的刚性和强度，而L-塑胶提供伸长所需的弹性。与此一致的是，在L-纤溶酶水平相对较低的细胞中，L-纤溶酶表达的升高促进了细胞的伸长并降低了突起密度。
Invadopodia and filopodia are dynamic, actin-based protrusions contributing to cancer cell migration, invasion, and metastasis. The force of actin bundles is essential for their protrusive activity. The bundling protein fascin is known to play a role in both invadopodia and filopodia. As it is more and more acknowledged that functionally related proteins cooperate, it is unlikely that only fascin bundles actin in these protrusions. Another interesting candidate is L-plastin, normally expressed in hematopoietic cells, but considered a common marker of many cancer types. We identified L-plastin as a new component of invadopodia, where it contributes to degradation and invasiveness. By means of specific, high-affinity nanobodies inhibiting bundling of fascin or L-plastin, we further unraveled their cooperative mode of action. We show that the bundlers cannot compensate for each other due to strikingly different bundling characteristics: L-plastin bundles are much thinner and less tightly packed. Composite bundles adopt an intermediate phenotype, with fascin delivering the rigidity and strength for protrusive force and structural stability, whereas L-plastin accounts for the flexibility needed for elongation. Consistent with this, elevated L-plastin expression promotes elongation and reduces protrusion density in cells with relatively lower L-plastin than fascin levels.