Store-independent activation of Orai1 by SPCA2 in mammary tumors

CA(2+) is an essential and ubiquitous second messenger. Changes in cytosolic CA(2+) trigger events critical for tumorigenesis, such as cellular motility, proliferation, and Apoptosis. We show that an isoform of Secretory Pathway CA(2+)-ATPase, SPCA2, is upregulated in breast cancer-derived cells and human breast tumors, and suppression of SPCA2 attenuates basal CA(2+) levels and tumorigenicity. Contrary to its conventional role in Golgi CA(2+) sequestration, expression of SPCA2 increased CA(2+) influx by a mechanism dependent on the store-operated CA(2+) channel Orai1. Unexpectedly, SPCA2-Orai1 signaling was independent of ER CA(2+) stores or STIM1 and STIM2 sensors and uncoupled from CA(2+)-ATPase activity of SPCA2. Binding of the SPCA2 amino terminus to Orai1 enabled access of its carboxyl terminus to Orai1 and activation of CA(2+) influx. Our findings reveal a signaling pathway in which the Orai1-SPCA2 complex elicits constitutive store-independent CA(2+) signaling that promotes tumorigenesis.