Ezrin regulates focal adhesion and invadopodia dynamics by altering calpain activity to promote breast cancer cell invasion.

Abstract

Up-regulation of the cytoskeleton linker protein ezrin frequently occurs in aggressive cancer types and is closely linked with metastatic progression. However, the underlying molecular mechanisms detailing how ezrin is involved in the invasive and metastatic phenotype remain unclear. Here we report a novel function of ezrin in regulating focal adhesion (FA) and invadopodia dynamics, two key processes required for efficient invasion to occur. We show that depletion of ezrin expression in invasive breast cancer cells impairs both FA and invadopodia turnover. We also demonstrate that ezrin-depleted cells display reduced calpain-mediated cleavage of the FA and invadopodia-associated proteins talin, focal adhesion kinase (FAK), and cortactin and reduced calpain-1-specific membrane localization, suggesting a requirement for ezrin in maintaining proper localization and activity of calpain-1. Furthermore, we show that ezrin is required for cell directionality, early lung seeding, and distant organ colonization but not primary tumor growth. Collectively our results unveil a novel mechanism by which ezrin regulates breast cancer cell invasion and metastasis.

• Authors: Victoria Hoskin, Alvin Szeto, Abdi Ghaffari, Peter A Greer, Graham P Côté, Bruce E Elliott
• Journal: Molecular biology of the cell (Mol Biol Cell) Vol. 26 Issue 19 Pg. 3464-79 (Oct 01 2015) ISSN: 1939-4586 [Electronic] United States
• PMID: 26246600 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Hoskin et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Chemical References

• Cytoskeletal Proteins
• Talin
• ezrin
• Focal Adhesion Protein-Tyrosine Kinases
• Calpain

Topics

• Animals
• Breast Neoplasms (enzymology, metabolism, pathology)
• Calpain (metabolism)
• Cell Adhesion (physiology)
• Cell Line, Tumor
• Cell Movement (physiology)
• Cytoskeletal Proteins (genetics, metabolism)
• Cytoskeleton (metabolism)
• Extracellular Matrix (metabolism)
• Female
• Focal Adhesion Protein-Tyrosine Kinases (metabolism)
• Focal Adhesions (metabolism)
• HEK293 Cells
• Heterografts
• Human Umbilical Vein Endothelial Cells
• Humans
• Mice
• Neoplasm Metastasis
• Podosomes (metabolism)
• Talin (metabolism)