Store-independent activation of Orai1 by SPCA2 in mammary tumors

Cell. 2010 Oct 1;143(1):84-98. doi: 10.1016/j.cell.2010.08.040.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Calcium Channels / metabolism*
  • Calcium Signaling*
  • Calcium-Transporting ATPases / metabolism*
  • Cell Line
  • Female
  • Gene Expression Profiling
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • ORAI1 Protein
  • Rats
  • Sequence Alignment
  • Transplantation, Heterologous


  • Calcium Channels
  • ORAI1 Protein
  • ORAI1 protein, human
  • ATP2C2 protein, human
  • Calcium-Transporting ATPases