Store-independent activation of Orai1 by SPCA2 in mammary tumors.
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.
Feng
Mingye
M
Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA.
Grice
Desma M
DM
Faddy
Helen M
HM
Nguyen
Nguyen
N
Leitch
Sharon
S
Wang
Yingyu
Y
Muend
Sabina
S
Kenny
Paraic A
PA
Sukumar
Saraswati
S
Roberts-Thomson
Sarah J
SJ
Monteith
Gregory R
GR
Rao
Rajini
R
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D000071740:ORAI1 Protein; D051381:Rats; D016415:Sequence Alignment; D014183:Transplantation, Heterologous
D015220:Calcium Channels; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C452183:ATP2C2 protein, human; D000252:Calcium-Transporting ATPases