Reciprocal regulation of actin cytoskeleton remodelling and cell migration by Ca2+ and Zn2+: 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 CA(2+) Here, we asked whether the H2O2-sensitive transient receptor potential melastatin 2 (TRPM2) CA(2+) channel serves as a molecular link between H2O2 and CA(2+) H2O2-mediated activation of TRPM2 channels induced filopodia formation, loss of actin stress fibres and disassembly of focal adhesions, leading to increased migration of HeLa and prostate Cancer (PC)-3 cells. Activation of TRPM2 channels, however, caused intracellular release of not only CA(2+) but also of Zn(2+) Intriguingly, elevation of intracellular Zn(2+) faithfully reproduced all of the effects of H2O2, whereas CA(2+) showed opposite effects. Interestingly, H2O2 caused increased trafficking of Zn(2+)-enriched lysosomes to the leading edge of migrating cells, presumably to impart polarisation of Zn(2+) location. Thus, our results indicate that a reciprocal interplay between CA(2+) and Zn(2+) regulates actin remodelling and cell migration; they call for a revision of the current notion that implicates an exclusive role for CA(2+) in cell migration.

Actin cytoskeleton dynamics; Ca2+; Cell migration; Focal adhesion; Lysosomal trafficking; TRPM2 channel; Zn2+.