Cab45S promotes cell proliferation through SERCA2b inhibition and Ca2+ signaling.

Cytosolic Ca2+, closely related to endoplasmic reticulum (ER) Ca2+, plays a critical role in regulating cell proliferation and tumorigenesis. However, the role of ER lumen proteins in regulating cytosolic Ca2+ level remains poorly understood. Here, we find that the Cab45S, localizes in the ER lumen, inhibits sarco/ER Ca2+-ATPase 2b (SERCA2b) activity through its first EF-hand domain directly binding to the intra-lumenal loop 4 of SERCA2b, and reduces ER Ca2+. STIM1 activation, induced by the Cab45S-dependent drop in ER Ca2+, together with the upregulation of the plasma membrane Ca2+ channel TRPC1 ultimately increases extracellular Ca2+ influx. Furthermore, increased cytosolic Ca2+ level elicits Ca2+-NFAT signaling and promotes cell proliferation. Consistently, in cervical carcinoma patients, Cab45S is upregulated. Thus, our data reveal that the ability of Cab45S to inhibit SERCA2b activity is crucial for its role as a modulator of cell proliferation and tumor growth.