Reciprocal regulation of actin cytoskeleton remodelling and cell migration by calcium and zinc: role of TRPM2 channels

Cell migration is a fundamental feature of tumour metastasis and angiogenesis. It is regulated by a variety of signalling molecules including H2O2 and Ca2+. Here, we asked if the H2O2-sensitive Transient Receptor Potential Melastatin 2 (TRPM2) calcium channel serves as a molecular link between H2O2 and Ca2+. H2O2 activation of TRPM2 channels induced filopodia formation, loss of actin stress fibres and disassembly of focal adhesions, leading to increased migration of HeLa and PC (prostate cancer)-3 cells. Activation of TRPM2 channels, however, caused intracellular release of not only Ca2+, but also Zn2+. Intriguingly, elevation of intracellular Zn2+ faithfully reproduced all of the effects of H2O2, while Ca2+ showed opposite effects. Interestingly, H2O2 caused increased trafficking of Zn2+-enriched lysosomes to the leading edge of migrating cells, presumably to impart polarisation of Zn2+. Thus our results indicate that a reciprocal interplay between Ca2+ and Zn2+ regulates actin remodelling and cell migration; they call for a revision of the current notion that implicates an exclusive role for Ca2+ in cell migration.