Metastasis enhancer PGRMC1 boosts store-operated Ca2+ entry by uncoiling Ca2+ sensor STIM1 for focal adhesion turnover and actomyosin formation

Abstract

Progesterone receptor membrane component 1 (PGRMC1), the overexpression of which reduces survivability of cancer patients, is essential for cell migration and metastasis. However, the intracellular signaling pathways involved are largely unknown. Here, we report that PGRMC1 promotes store-operated Ca²⁺ entry (SOCE) as a functional interactor of stromal interaction molecule 1 (STIM1). PGRMC1 was repeatedly detected as an interactor of STIM1-Orai1 complex via complementation-dependent in situ labeling. Genetic depletion of PGRMC1 decreased SOCE and impaired activation of the nuclear factor of the activated T cell (NFAT) pathway. Mechanistically, PGRMC1 directly bound to the coiled-coil domain of STIM1, promoting STIM1 conformational switch. In breast cancer cells, PGRMC1 depletion reduced epidermal growth factor (EGF)-induced SOCE and disrupted focal adhesion turnover and actomyosin formation. These findings identify PGRMC1 as an essential regulator of Ca²⁺ signaling in breast cancer cells, providing a target for treating cancer metastasis and an insight for dissecting various PGRMC1/SOCE-induced biological processes.

Keywords: Ca(2+) signaling; ER-PM junctions; Orai1; PGRMC1; SOCE; STIM1; actomyosin; breast cancer; cell migration; focal adhesion.