Abstract
The common currency of epithelial differentiation and homeostasis is calcium, stored primarily in the endoplasmic reticulum, rationed according to need, and replenished from the extracellular milieu via store-operated calcium entry (SOCE). This currency is disbursed by the IP3 receptor in response to diverse extracellular signals. The rate of release is governed by regulators of proliferation, autophagy, survival, and programmed cell death, the strength of the signal leading to different outcomes. Intracellular calcium acts chiefly through intermediates such as calmodulin that regulates growth factor receptors such as epidermal growth factor receptor (EGFR), actin polymerization, and adherens junction assembly and maintenance. Here we review this machinery and its role in differentiation, then consider how cancer cells subvert it to license proliferation, resist anoikis, and enable metastasis, either by modulating the level of intracellular calcium or its downstream targets or effectors such as EGFR, E-cadherin, IQGAP1, TMEM16A, CLCA2, and TRPA1. Implications are considered for the roles of E-cadherin and growth factor receptors in circulating tumor cells and metastasis. The discovery of novel, cell type-specific modulators and effectors of calcium signaling offers new possibilities for cancer chemotherapy.
Highlights
Calcium plays a unique role among all the ions that exist in the fluids in and around a living cell to maintain cellular homeostasis and other physiological functions [1]
Most of the time low cytosolic calcium levels persist in cells which is leveraged in the form of small calcium ion fluxes creating greater cellular responses [2]
How does iCa2+ influence E-cadherin surface localization? As E-cadherin is translated into the ER, it is assembled into a complex with beta catenin, and this complex is bound by IQGAP1
Summary
Calcium plays a unique role among all the ions that exist in the fluids in and around a living cell to maintain cellular homeostasis and other physiological functions [1]. As a potent signaling agent, Ca2+ must be sequestered from its targets in the cytosol before the time of action This is accomplished by ATP-driven SERCA (Sarco/ER Ca2+ - ATPase) pumps in the membrane of the ER, the principal repository of iCa2+ (intracellular calcium; Figure 1) [4]. In the membrane Ca2+ channel (Orai1) in a process termed store-operated calcium entry (SOCE) [7]. Ca -binding proteins in the cytosol stimulate a host of cell typetype-dependent signaling pathways. C; Ca by disrupting membrane potential and releasing cytochrome C; Ca transfer to is mitochondria tightly modulated, either positively either or negatively, by or regulators of proliferation, and is tightly modulated, positively negatively, by regulatorsautophagy, of proliferation, death such asand the death.
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