MT1-MMP 依赖性侵袭受 TI-VAMP/VAMP7 调控。
MT1-MMP-dependent invasion is regulated by TI-VAMP/VAMP7.
作者信息
Steffen Anika, Le Dez Gaëlle, Poincloux Renaud, Recchi Chiara, Nassoy Pierre, Rottner Klemens, Galli Thierry, Chavrier Philippe
机构信息
Institut Curie, Centre de Recherche, 26 rue d'Ulm, 75248 Paris, Cedex 05, France.
出版信息
Curr Biol. 2008 Jun 24;18(12):926-31. doi: 10.1016/j.cub.2008.05.044.
Proteolytic degradation of the extracellular matrix (ECM) is one intrinsic property of metastatic tumor cells to breach tissue barriers and to disseminate into different tissues. This process is initiated by the formation of invadopodia, which are actin-driven, finger-like membrane protrusions. Yet, little is known on how invadopodia are endowed with the functional machinery of proteolytic enzymes [1, 2]. The key protease MT1-MMP (membrane type 1-matrix metalloproteinase) confers proteolytic activity to invadopodia and thus invasion capacity of cancer cells [3-6]. Here, we report that MT1-MMP-dependent matrix degradation at invadopodia is regulated by the v-SNARE TI-VAMP/VAMP7, hence providing the molecular inventory mediating focal degradative activity of cancer cells. As observed by TIRF microscopy, MT1-MMP-mCherry and GFP-VAMP7 were simultaneously detected at proteolytic sites. Functional ablation of VAMP7 decreased the ability of breast cancer cells to degrade and invade in a MT1-MMP-dependent fashion. Moreover, the number of invadopodia was dramatically decreased in VAMP7- and MT1-MMP-depleted cells, indicative of a positive-feedback loop in which the protease as a cargo of VAMP7-targeted transport vesicles regulates maturation of invadopodia. Collectively, these data point to a specific role of VAMP7 in delivering MT1-MMP to sites of degradation, maintaining the functional machinery required for invasion.
细胞外基质(ECM)的蛋白水解降解是转移性肿瘤细胞突破组织屏障并扩散到不同组织的一种内在特性。这个过程由侵袭伪足的形成启动,侵袭伪足是由肌动蛋白驱动的手指状膜突起。然而,关于侵袭伪足如何具备蛋白水解酶的功能机制却知之甚少[1,2]。关键蛋白酶MT1-MMP(膜型1-基质金属蛋白酶)赋予侵袭伪足以蛋白水解活性,从而赋予癌细胞侵袭能力[3-6]。在此,我们报道侵袭伪足处依赖MT1-MMP的基质降解受v-SNARE TI-VAMP/VAMP7调控,从而提供了介导癌细胞局部降解活性的分子机制。通过全内反射荧光显微镜(TIRF显微镜)观察发现,MT1-MMP-樱桃红荧光蛋白和绿色荧光蛋白标记的VAMP7在蛋白水解位点同时被检测到。VAMP7的功能缺失降低了乳腺癌细胞以依赖MT1-MMP的方式进行降解和侵袭的能力。此外,在VAMP7和MT1-MMP缺失的细胞中,侵袭伪足的数量显著减少,这表明存在一个正反馈环,其中作为VAMP7靶向运输囊泡货物的蛋白酶调节侵袭伪足的成熟。总的来说,这些数据表明VAMP7在将MT1-MMP递送到降解位点、维持侵袭所需的功能机制方面具有特定作用。