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PMID: 20887894 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Store-independent activation of Orai1 by SPCA2 in mammary tumors.

Cell ·Vol. 143 ·No. 1 ·2010-10-01 ·Pages 84-98

Feng M, Grice DM, Faddy HM, Nguyen N, Leitch S, Wang Y, Muend S, Kenny PA, Sukumar S, Roberts-Thomson SJ, Monteith GR, Rao R

Abstract

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.

MeSH Terms
Amino Acid Sequence Animals Breast Neoplasms/genetics,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
Chemicals
Calcium Channels ORAI1 Protein ORAI1 protein, human ATP2C2 protein, human Calcium-Transporting ATPases
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Feng Mingye
Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA.
Grice Desma M
Faddy Helen M
Nguyen Nguyen
Leitch Sharon
Wang Yingyu
Muend Sabina
Kenny Paraic A
Sukumar Saraswati
Roberts-Thomson Sarah J
Monteith Gregory R
Rao Rajini
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2010.08.040
Published
2010-10-01
Pages
84-98
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2950964
Subset
IM
Grants
NIGMS NIH HHS · R01 GM062142 · United States
NIGMS NIH HHS · GM62142 · United States
Corrections
CommentIn
PMID: 21080584
External Links
PubMed source DOI: 10.1016/j.cell.2010.08.040 PMC Full Text View journal details
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