Actin-associated protein palladin promotes tumor cell invasion by linking extracellular matrix degradation to cell cytoskeleton.
Actin-associated protein palladin promotes tumor cell invasion by linking extracellular matrix degradation to cell cytoskeleton.
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DOI：
10.1091/mbc.e13-11-0667
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发表时间：
2014-09-01
影响因子：
3.3
通讯作者：
Lehti K
中科院分区：
文献类型：
--
作者：
von Nandelstadh P;Gucciardo E;Lohi J;Li R;Sugiyama N;Carpen O;Lehti K
这项研究发现了关键细胞表面胶原酶MT1-MMP和动态肌动蛋白结合蛋白Palladin之间的一种新的蛋白质相互作用，该蛋白将细胞外基质的降解与细胞骨架动力学和迁移信号联系起来，从而促进乳腺癌细胞的间质侵袭。基底细胞样癌以预后不良和转移频繁为特征，与上皮向间充质转化有关。在这个过程中，癌细胞经历细胞骨架重组和上调膜型1基质金属蛋白酶(MT1-MMP；MMP14)，该酶在基于肌动蛋白的伪足中发挥作用，通过降解细胞外基质来驱动侵袭。然而，基质蛋白降解与肌动蛋白细胞骨架在细胞侵袭中的偶联机制尚不清楚。在酵母双杂交筛选MT1-MMP胞浆尾结合蛋白的基础上，我们在这里发现了一种新的由Src调控的蛋白相互作用，该蛋白发生在动态细胞骨架蛋白Palladin和MT1-MMP间。这些蛋白在侵袭性人基底细胞样乳腺癌和相应的细胞系中共表达，它们在相同的基质接触和降解膜复合体中相关联。90 kDa Palladin亚型的沉默和过度表达揭示了与MT1-MMP相互作用在细胞周围基质降解和间质肿瘤细胞侵袭中的重要作用，而在MT1-MMP阴性细胞中，Palladin过表达不足以促进侵袭。此外，这种入侵被含有免疫球蛋白结构域的Palladin片段以显性-负向的方式抑制，该片段缺乏动态支架和Src结合域。这些结果确定了一种新的蛋白质相互作用，将基质降解与细胞骨架动力学和间充质细胞侵袭中的迁移信号联系起来。
This study identifies a novel protein interaction between the key cell-surface collagenase MT1-MMP and the dynamic actin-binding protein palladin, which links extracellular matrix degradation to cytoskeletal dynamics and migration signaling, thus promoting mesenchymal invasion of breast carcinoma cells. Basal-like breast carcinomas, characterized by unfavorable prognosis and frequent metastases, are associated with epithelial-to-mesenchymal transition. During this process, cancer cells undergo cytoskeletal reorganization and up-regulate membrane-type 1 matrix metalloproteinase (MT1-MMP; MMP14), which functions in actin-based pseudopods to drive invasion by extracellular matrix degradation. However, the mechanisms that couple matrix proteolysis to the actin cytoskeleton in cell invasion have remained unclear. On the basis of a yeast two-hybrid screen for the MT1-MMP cytoplasmic tail-binding proteins, we identify here a novel Src-regulated protein interaction between the dynamic cytoskeletal scaffold protein palladin and MT1-MMP. These proteins were coexpressed in invasive human basal-like breast carcinomas and corresponding cell lines, where they were associated in the same matrix contacting and degrading membrane complexes. The silencing and overexpression of the 90-kDa palladin isoform revealed the functional importance of the interaction with MT1-MMP in pericellular matrix degradation and mesenchymal tumor cell invasion, whereas in MT1-MMP–negative cells, palladin overexpression was insufficient for invasion. Moreover, this invasion was inhibited in a dominant-negative manner by an immunoglobulin domain–containing palladin fragment lacking the dynamic scaffold and Src-binding domains. These results identify a novel protein interaction that links matrix degradation to cytoskeletal dynamics and migration signaling in mesenchymal cell invasion.