Plasma membrane Ca 2+ pump isoform 4 function in cell migration and cancer metastasis.

The Ca 2+ ion is a universal second messenger involved in many vital physiological functions including cell migration and development. To fulfill these tasks cytosolic Ca 2+ concentration is tightly controlled, and this involves an intricate functional balance between a variety of channels and pumps of the Ca 2+ signaling machinery. Among these proteins, plasma membrane Ca 2+ ATPases (PMCAs) represent the major high-affinity Ca 2+ extrusion systems in the cell membrane that are effective in maintaining free Ca 2+ concentration at exceedingly low cytosolic levels, which is essential for normal cell function. An imbalance in Ca 2+ signaling can lead to pathogenic consequences including cancer and metastasis. Recent studies highlighted the role of PMCAs in cancer progression and showed that a particular variant, PMCA4b is downregulated in certain cancer types, causing delayed attenuation of the Ca 2+ signal. It has also been shown that loss of PMCA4b leads to increased migration and metastasis of melanoma and gastric cancer cells. In contrast, increased PMCA4 expression was reported in pancreatic ductal adenocarcinoma that coincided with increased cell migration and shorter patient survival suggesting distinct roles of PMCA4b in various tumor types and/or different stages of tumor development. The recently discovered interaction of PMCAs with basigin (BSG), an extracellular matrix metalloproteinase inducer (EMMPRIN), may provide further insights into our understanding on the specific roles of PMCA4b in tumor progression and cancer metastasis. Abstract figure legend PMCAs are key regulators of low cytosolic Ca 2+ concentration in mammalian cells. In cancer, dysregulation of Ca 2+ homeostasis is involved in cell migration and metastasis. Transcription, expression, localization, trafficking, and activity of the PMCA4 isoform are reported to vary in different cancer cells. As a result of an imbalance in PMCA4 stability, the overall ability of cells to migrate/metastasize changes through its effect on actin cytoskeleton remodeling, cell shape, Ca 2+ gradient formation, and consequent cell polarization, cell-cell connections, cell motility, focal adhesion turnover, EMT and local angiogenesis. This article is protected by copyright. All rights reserved.