Store-independent activation of orai1 by SPCA2 in mammary tumors

Ca²⁺ is an essential and ubiquitous second messenger. Changes in cytosolic Ca²⁺ trigger events critical for tumorigenesis, such as cellular motility, proliferation, and apoptosis. We show that an isoform of Secretory Pathway Ca²⁺-ATPase, SPCA2, is upregulated in breast cancer-derived cells and human breast tumors, and suppression of SPCA2 attenuates basal Ca²⁺ levels and tumorigenicity. Contrary to its conventional role in Golgi Ca²⁺ sequestration, expression of SPCA2 increased Ca²⁺ influx by a mechanism dependent on the store-operated Ca²⁺ channel Orai1. Unexpectedly, SPCA2-Orai1 signaling was independent of ER Ca²⁺ stores or STIM1 and STIM2 sensors and uncoupled from Ca²⁺-ATPase activity of SPCA2. Binding of the SPCA2 amino terminus to Orai1 enabled access of its carboxyl terminus to Orai1 and activation of Ca²⁺ influx. Our findings reveal a signaling pathway in which the Orai1-SPCA2 complex elicits constitutive store-independent Ca²⁺ signaling that promotes tumorigenesis.