Abstract
Cell migration is one of the many processes orchestrated by calcium (Ca2+) signaling, and its dysregulation drives the increased invasive and metastatic potential of cancer cells. The ability of Ca2+ to function effectively as a regulator of migration requires the generation of temporally complex signals within spatially restricted microdomains. The generation and maintenance of these Ca2+ signals require a specific structural architecture and tightly regulated communication between the extracellular space, intracellular organelles, and cytoplasmic compartments. New insights into how Ca2+ microdomains are shaped by interorganellar Ca2+ communication have shed light on how Ca2+ coordinates cell migration by directing cellular polarization and the rearrangement of structural proteins. Importantly, we are beginning to understand how cancer subverts normal migration through the activity of oncogenes and tumor suppressors that impinge directly on the physiological function or expression levels of Ca2+ signaling proteins. In this review, we present and discuss research at the forefront of interorganellar Ca2+ signaling as it relates to cell migration, metastasis, and cancer progression, with special focus on endoplasmic reticulum-to-mitochondrial Ca2+ transfer.
Highlights
Pathology is frequently associated with the dysregulation of intracellular calcium (Ca2+) signaling [1]
Mitochondrial Calcium, Invasion and Metastasis oncogenic Ras [8, 9] and the tumor suppressors promyelocytic leukemia (PML) [10], p53 [11], and BRCA1 [12] can all regulate apoptosis by impinging on the Ca2+ signal. Many of these proteins are enriched in spatially restricted domains created by the close apposition between the endoplasmic reticulum (ER) and the mitochondria, known as mitochondria-associated membranes (MAMs), where they function to modulate the flow of Ca2+ from the ER to mitochondria
The molecular identification of the store-operated Ca2+ entry (SOCE) and mitochondrial Ca2+ uniporter (MCU) machinery, the introduction of powerful molecular tools, and the evolution of cancer genetics have all contributed to developing our understanding of how Ca2+ signals regulate cancer cell invasion and metastasis
Summary
Physiology and Biophysics, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States. The ability of Ca2+ to function effectively as a regulator of migration requires the generation of temporally complex signals within spatially restricted microdomains. The generation and maintenance of these Ca2+ signals require a specific structural architecture and tightly regulated communication between the extracellular space, intracellular organelles, and cytoplasmic compartments. New insights into how Ca2+ microdomains are shaped by interorganellar Ca2+ communication have shed light on how Ca2+ coordinates cell migration by directing cellular polarization and the rearrangement of structural proteins. We are beginning to understand how cancer subverts normal migration through the activity of oncogenes and tumor suppressors that impinge directly on the physiological function or expression levels of Ca2+ signaling proteins. We present and discuss research at the forefront of interorganellar Ca2+ signaling as it relates to cell migration, metastasis, and cancer progression, with special focus on endoplasmic reticulum-to-mitochondrial Ca2+ transfer.
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