Martín-Villar E, Borda-d'Agua B, Carrasco-Ramirez P, Renart J, Parsons M, Quintanilla M, Jones G E
Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
Randall Division of Cell & Molecular Biophysics, King's College London, London, UK.
Oncogene. 2015 Aug 20;34(34):4531-44. doi: 10.1038/onc.2014.388. Epub 2014 Dec 8.
Invadopodia are actin-rich cell membrane projections used by invasive cells to penetrate the basement membrane. Control of invadopodia stability is critical for efficient degradation of the extracellular matrix (ECM); however, the underlying molecular mechanisms remain poorly understood. Here, we uncover a new role for podoplanin, a transmembrane glycoprotein closely associated with malignant progression of squamous cell carcinomas (SCCs), in the regulation of invadopodia-mediated matrix degradation. Podoplanin downregulation in SCC cells impairs invadopodia stability, thereby reducing the efficiency of ECM degradation. We report podoplanin as a novel component of invadopodia-associated adhesion rings, where it clusters prior to matrix degradation. Early podoplanin recruitment to invadopodia is dependent on lipid rafts, whereas ezrin/moesin proteins mediate podoplanin ring assembly. Finally, we demonstrate that podoplanin regulates invadopodia maturation by acting upstream of the ROCK-LIMK-Cofilin pathway through the control of RhoC GTPase activity. Thus, podoplanin has a key role in the regulation of invadopodia function in SCC cells, controlling the initial steps of cancer cell invasion.
侵袭性伪足是富含肌动蛋白的细胞膜突起，侵袭性细胞利用其穿透基底膜。控制侵袭性伪足的稳定性对于有效降解细胞外基质（ECM）至关重要；然而，其潜在的分子机制仍知之甚少。在这里，我们揭示了血小板反应蛋白-1（一种与鳞状细胞癌（SCC）恶性进展密切相关的跨膜糖蛋白）在调节侵袭性伪足介导的基质降解中的新作用。SCC细胞中血小板反应蛋白-1的下调会损害侵袭性伪足的稳定性，从而降低ECM降解效率。我们报道血小板反应蛋白-1是侵袭性伪足相关粘附环的一种新成分，它在基质降解之前聚集。血小板反应蛋白-1早期募集到侵袭性伪足依赖于脂筏，而埃兹蛋白/膜突蛋白介导血小板反应蛋白-1环的组装。最后，我们证明血小板反应蛋白-1通过控制RhoC GTP酶活性在ROCK-LIMK-丝切蛋白途径的上游起作用，从而调节侵袭性伪足的成熟。因此，血小板反应蛋白-1在SCC细胞侵袭性伪足功能的调节中起关键作用，控制癌细胞侵袭的初始步骤。
