Store-independent activation of orai1 by SPCA2 in mammary tumors

Mingye Feng, Desma M. Grice, Helen M. Faddy, Nguyen Nguyen, Sharon Leitch, Yingyu Wang, Sabina Muend, Paraic A. Kenny, Saraswati Sukumar, Sarah J. Roberts-Thomson, Gregory R. Monteith, Rajini Rao

Research output: Contribution to journalArticle

175 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)84-98
Number of pages15
JournalCell
Volume143
Issue number1
DOIs
StatePublished - Oct 1 2010

Keywords

  • Cellbio
  • Humdisease
  • Signaling

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Feng, M., Grice, D. M., Faddy, H. M., Nguyen, N., Leitch, S., Wang, Y., Muend, S., Kenny, P. A., Sukumar, S., Roberts-Thomson, S. J., Monteith, G. R., & Rao, R. (2010). Store-independent activation of orai1 by SPCA2 in mammary tumors. Cell, 143(1), 84-98. https://doi.org/10.1016/j.cell.2010.08.040