Plasma Membrane Ca ATPase Activity Enables Sustained Store-operated Ca Entry in the Absence of a Bulk Cytosolic Ca Rise.

In many cell types, the rise in cytosolic Ca due to opening of Ca release-activated Ca (CRAC) channels drives a plethora of responses, including secretion, motility, energy production, and gene expression. The amplitude and time course of the cytosolic Ca rise is shaped by the rates of Ca entry into and removal from the cytosol. However, an extended bulk Ca rise is toxic to cells.

AKAP79 Orchestrates a Cyclic AMP Signalosome Adjacent to Orai1 Ca Channels.

To ensure specificity of response, eukaryotic cells often restrict signalling molecules to sub-cellular regions. The Ca nanodomain is a spatially confined signal that arises near open Ca channels. Ca nanodomains near store-operated Orai1 channels stimulate the protein phosphatase calcineurin, which activates the transcription factor NFAT1, and both enzyme and target are initially attached to the plasma membrane through the scaffolding protein AKAP79.

Specific N-cadherin-dependent pathways drive human breast cancer dormancy in bone marrow.

The challenge for treating breast cancer (BC) is partly due to long-term dormancy driven by cancer stem cells (CSCs) capable of evading immune response and resist chemotherapy. BC cells show preference for the BM, resulting in poor prognosis. CSCs use connexin 43 (Cx43) to form gap junctional intercellular communication with BM niche cells, fibroblasts, and mesenchymal stem cells (MSCs).

Mesenchymal Stem Cell-Secreted Extracellular Vesicles Instruct Stepwise Dedifferentiation of Breast Cancer Cells into Dormancy at the Bone Marrow Perivascular Region.

In the bone marrow (BM), breast cancer cells (BCC) can survive in dormancy for decades as cancer stem cells (CSC), resurging as tertiary metastasis. The endosteal region where BCCs exist as CSCs poses a challenge to target them, mostly due to the coexistence of endogenous hematopoietic stem cells. This study addresses the early period of dormancy when BCCs enter BM at the perivascular region to begin the transition into CSCs, which we propose as the final step in dormancy.

Signaling through Ca Microdomains from Store-Operated CRAC Channels.

Calcium (Ca) ion microdomains are subcellular regions of high Ca concentration that develop rapidly near open Ca channels in the plasma membrane or internal stores and generate local regions of high Ca concentration. These microdomains are remarkably versatile in that they activate a range of responses that differ enormously in both their temporal and spatial profile. In this review, we describe how Ca microdomains generated by store-operated calcium channels, a widespread and conserved Ca entry pathway, stimulate different signaling pathways, and how the spatial extent of a Ca microdomain can be influenced by Ca ATPase pumps.