Journal
ONCOGENE
Volume 34, Issue 34, Pages 4531-4544Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2014.388
Keywords
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Funding
- Cancer Research UK [C7125/A9926, A13651]
- Medical Research Council [G0401026]
- Spanish Ministry of Economy and Competitiveness [SAF 2010-19152/SAF2013-46183R]
- Community of Madrid [S2010/BMD-2359]
- Fundacion Cientifica Asociacion Espanola Contra el Cancer (AECC)
- Medical Research Council [G0401026] Funding Source: researchfish
- MRC [G0401026, G1100041] Funding Source: UKRI
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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.
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