title: Store-independent activation of Orai1 by SPCA2 in mammary tumors.
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.
authors.affiliation: Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Mingye
authors.initials: M
authors.lastname: Feng
authors.forename: Desma M
authors.initials: DM
authors.lastname: Grice
authors.forename: Helen M
authors.initials: HM
authors.lastname: Faddy
authors.forename: Nguyen
authors.initials: N
authors.lastname: Nguyen
authors.forename: Sharon
authors.initials: S
authors.lastname: Leitch
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Wang
authors.forename: Sabina
authors.initials: S
authors.lastname: Muend
authors.forename: Paraic A
authors.initials: PA
authors.lastname: Kenny
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Roberts-Thomson
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Monteith
authors.forename: Rajini
authors.initials: R
authors.lastname: Rao
mesh_terms: 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
chemical_list: D015220:Calcium Channels; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C452183:ATP2C2 protein, human; D000252:Calcium-Transporting ATPases