MT1-MMP- and Cdc42-dependent signaling co-regulate cell invasion and tunnel formation in 3D collagen matrices
MT1-MMP- and Cdc42-dependent signaling co-regulate cell invasion and tunnel formation in 3D collagen matrices
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DOI：
10.1242/jcs.050724
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发表时间：
2009-12-15
影响因子：
4
通讯作者：
Davis, George E.
中科院分区：
文献类型：
--
作者：
Fisher, Kevin E.;Sacharidou, Anastasia;Davis, George E.
复杂的信号事件控制着三维(3D)细胞外基质中的肿瘤侵袭。最近的证据表明，细胞利用基质金属蛋白酶(MMPs)依赖和非依赖的方式来遍历3D基质。在这里，我们证明了溶血磷脂酸诱导的HT1080细胞侵袭需要膜-1型(MT1)-基质金属蛋白酶(MMP1)介导的胶原酶分解来产生细胞核宽度的基质管道。我们将这些空间定义为单细胞入侵隧道(SCIT)。一旦建立，细胞可以在SCITs内以一种不依赖于基质金属蛋白酶的方式迁移。内皮细胞、平滑肌细胞和成纤维细胞在侵袭性事件中也会产生SCIT，这表明SCIT的形成代表了3D基质中细胞运动的基本机制。在SCIT形成过程中需要协调的蜂窝信令事件。MT1-MMPs、CDC42及其相关的下游效应因子如MRCK(肌营养不良相关的CDC42结合蛋白)和PAC4(p21蛋白活化蛋白4)、蛋白激酶Ca和Rho相关的卷曲-含有蛋白的蛋白激酶(ROCK-1和ROCK-2)协调SCIT形成所需的信号转导。最后，我们证明MT1-MMPs和CDC42是共同关联的侵袭信号复合体的基本成分，该复合体控制3D胶原基质的定向单细胞侵袭。
Complex signaling events control tumor invasion in three-dimensional (3D) extracellular matrices. Recent evidence suggests that cells utilize both matrix metalloproteinase (MMP)-dependent and MMP-independent means to traverse 3D matrices. Herein, we demonstrate that lysophosphatidic-acid-induced HT1080 cell invasion requires membrane-type-1 (MT1)-MMP-mediated collagenolysis to generate matrix conduits the width of a cellular nucleus. We define these spaces as single-cell invasion tunnels (SCITs). Once established, cells can migrate within SCITs in an MMP-independent manner. Endothelial cells, smooth muscle cells and fibroblasts also generate SCITs during invasive events, suggesting that SCIT formation represents a fundamental mechanism of cellular motility within 3D matrices. Coordinated cellular signaling events are required during SCIT formation. MT1-MMP, Cdc42 and its associated downstream effectors such as MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) and Pak4 (p21 protein-activated kinase 4), protein kinase Ca and the Rho-associated coiled-coil-containing protein kinases (ROCK-1 and ROCK-2) coordinate signaling necessary for SCIT formation. Finally, we show that MT1-MMP and Cdc42 are fundamental components of a co-associated invasionsignaling complex that controls directed single-cell invasion of 3D collagen matrices.