Cell migration is a key process in cancer metastasis, allowing malignant cells to spread from the primary tumor to distant organs. At the molecular level, migration is the result of several coordinated events involving mechanical forces and cellular signaling, where the second messenger Ca²⁺ plays a pivotal role. Therefore, elucidating the regulation of intracellular Ca²⁺ levels is key for a complete understanding of the mechanisms controlling cellular migration. In this regard, understanding the function of Transient Receptor Potential (TRP) channels, which are fundamental determinants of Ca²⁺ signaling, is critical to uncovering mechanisms of mechanotransduction during cell migration and, consequently, in pathologies closely linked to it, such as cancer. Here, we review recent studies on the association between TRP channels and migration-related mechanotransduction events, as well as in the involvement of TRP channels in the migration-dependent pathophysiological process of metastasis.

Cell migration is critical for several physiological and pathophysiological processes. It depends on the coordinated action of kinases, phosphatases, Rho-GTPases proteins, and Ca²⁺ signaling. Interestingly, ubiquitination events have emerged as regulatory elements of migration. Thus, the role of proteins involved in ubiquitination processes could be relevant to a complete understanding of pro-migratory mechanisms. KCTD5 is a member of Potassium Channel Tetramerization Domain (KCTD) proteins that have been proposed as a putative adaptor for Cullin3-E3 ubiquitin ligase and a novel regulatory protein of TRPM4 channels. Here, we study whether KCTD5 participates in cell migration-associated mechanisms, such as focal adhesion dynamics and cellular spreading. Our results show that KCTD5 CRISPR/Cas9- and shRNA-based depletion in B16-F10 cells promoted an increase in cell migration and cell spreading, and a decrease in the focal adhesion area, consistent with an increased focal adhesion disassembly rate. The expression of a dominant-negative mutant of Rho-GTPases Rac1 precluded the KCTD5 depletion-induced increase in cell spreading. Additionally, KCTD5 silencing decreased the serum-induced Ca²⁺ response, and the reversion of this with ionomycin abolished the KCTD5 knockdown-induced decrease in focal adhesion size. Together, these data suggest that KCTD5 acts as a regulator of cell migration by modulating cell spreading and focal adhesion dynamics through Rac1 activity and Ca²⁺ signaling, respectively.