Plasma membrane Ca²⁺ pump isoform 4 function in cell migration and cancer metastasis

The Ca²⁺ ion is a universal second messenger involved in many vital physiological functions including cell migration and development. To fulfil these tasks the cytosolic Ca²⁺ concentration is tightly controlled, and this involves an intricate functional balance between a variety of channels and pumps of the Ca²⁺ signalling machinery. Among these proteins, plasma membrane Ca²⁺ ATPases (PMCAs) represent the major high-affinity Ca²⁺ extrusion systems in the cell membrane that are effective in maintaining free Ca²⁺ concentration at exceedingly low cytosolic levels, which is essential for normal cell function. An imbalance in Ca²⁺ signalling can have pathogenic consequences including cancer and metastasis. Recent studies have highlighted the role of PMCAs in cancer progression and have shown that a particular variant, PMCA4b, is downregulated in certain cancer types, causing delayed attenuation of the Ca²⁺ signal. It has also been shown that loss of PMCA4b leads to increased migration and metastasis of melanoma and gastric cancer cells. In contrast, an increased PMCA4 expression has been reported in pancreatic ductal adenocarcinoma that coincided with increased cell migration and shorter patient survival, suggesting distinct roles of PMCA4b in various tumour types and/or different stages of tumour development. The recently discovered interaction of PMCAs with basigin, an extracellular matrix metalloproteinase inducer, may provide further insights into our understanding of the specific roles of PMCA4b in tumour progression and cancer metastasis.