The calcium pump PMCA4b promotes epithelial cell polarization and lumen formation

Abstract

AbstractLoss of epithelial cell polarity is a hallmark of carcinogenesis, in which Ca2+signaling plays a role. Here we demonstrate that the plasma membrane Ca2+pump PMCA4 is downregulated in luminal breast cancer, and this is associated with shorter relapse-free survival of patients with luminal A and B1 sub-type tumors. We find thatin vitrosilencing of PMCA4 in MCF-7 breast cancer cells induces internalization of E-cadherin and Dlg1 leading to a severe loss of cell polarity while re-expression of the b variant of PMCA4 restores cell polarity and promotes lumen formation mediated by the Arf6-trafficking pathway. We also demonstrate via anin vivomodel usingDrosophila melanogasterthat silencing of the singlepmcagene destroys lumen morphology in the larval salivary gland suggesting a conserved role of PMCAs in lumen morphogenesis. Additionally, enhanced secretory vesicle accumulation in PMCA(4)-deficient cells indicates a profound secretion defect bothin vitroandin vivo. Our findings point to a novel role of PMCA4 in restoring epithelial cell polarity, and maintaining normal glandular tissue architecture.