Stanniocalcin 2 modulates store-operated calcium entry

The regulation of cellular Ca2+ homeostasis is essential for innumerable physiological and pathological processes. Stanniocalcin 1, a secreted glycoprotein hormone originally described in fish, is a well-established endocrine regulator of gill Ca2+ uptake during hypercalcemia. While there are two mammalian Stanniocalcin homologs (Stc1 and Stc2), their precise molecular function remains unknown. Notably, STC2 is a pro-survival component of the unfolded protein response. Here, I demonstrate a cell-intrinsic role for STC2 in the regulation of store-operated Ca2+ entry (SOCE). Fibroblasts cultured from Stc2 -/- mice accumulate higher levels of cytosolic Ca 2+ following endoplasmic reticulum (ER) Ca2+ store depletion, specifically due to an increase in extracellular Ca2+ influx through store-operated Ca2+ channels (SOCs). Knockdown of STC2 expression in a hippocampal cell line also potentiates SOCE, and overexpression of STC2 attenuates SOCE. Moreover, STC2 interacts with the ER calcium sensor STIM1, which activates SOCs following ER store depletion. These results define a novel molecular function for STC2 as a negative modulator of SOCE and provide the first direct evidence for the regulation of Ca2+ homeostasis by mammalian STC2. Importantly, my findings implicate modulation of SOCE through STC2 expression as an integral cytoprotective response to oxidative stress. I have also identified a SOCE-independent role for STC2 in cellular motility, a function which may have important pathological consequences in human cancers. Finally, I have also investigated the potential role of STC2 and SOCE in the pathogenesis of Alzheimer's disease. Our results show that loss of STC2 expression can affect levels of Abeta in transgenic mice and lead to changes in APP processing in vitro. Changes in APP processing can also be induced through modulation of SOCE, suggesting that STC2 mediated regulation of SOCE may be relevant to AD pathogenesis.