- TRPM7: Ca2+ signaling, actomyosin remodeling and metastasis
F.N. van Leeuwen
- Award date
- 9 January 2014
- Number of pages
- Document type
- PhD thesis
- Faculty of Science (FNWI)
- Swammerdam Institute for Life Sciences (SILS)
TRPM7 is an intriguing bifunctional protein that constitutes the fusion between a cation channel and a serine/threonine protein kinase domain. It has been proposed to function in several fundamental physiological processes, including cell adhesion and migration. Biological dysfunctioning of TRPM7 has in turn been associated with several diseases, such as cancer. We show that TRPM7 contributes to the migration of tumor cells in vitro and the formation of metastasis in vivo. Moreover, high(er) TRPM7 mRNA levels correlate with poor disease outcome and metastasis formation in two independent breast cancer cohorts, independently of other clinical parameters such as tumor size. Cell proliferation of breast cancer cells (MDA-MB-231) and neuroblastoma cells (N1E-115) in cell culture conditions was not affected by TRPM7 knockdown and overexpression, respectively, neither was the size of metastases in experimental metastasis assays. We demonstrate that manipulating the expression levels of TRPM7 particularly affects cell-matrix adhesions in both breast cancer cells and neuroblastoma cells. TRPM7 downregulation in breast cancer cells results in a contractile phenotype and increased focal adhesion numbers. TRPM7 overexpression in neuroblastoma cells, on the other hand, is associated with increased cell flattening (a ‘relaxed morphology’) and cell-adhesive properties, accompanied by the formation of invadosomes. We find that TRPM7 acts as a regulator of cellular tension, cell adhesion dynamics and migration independent from mediating (localized) Ca2+-signaling. Rather our proteomics results and our analyses using the TRPM7 inhibitor Waixenicin-A suggest that TRPM7 may control these processes by functioning as a scaffold.
- Research conducted at: Universiteit van Amsterdam
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