SPCA2 couples Ca2+influx via Orai1 to Ca2+uptake into the Golgi/secretory pathway.
Dysregulation of the Golgi/Secretory Pathway Ca2+transport ATPase SPCA2 is implicated in breast cancer. During lactation and in luminal breast cancer types, SPCA2 interacts with the plasma membrane Ca2+channel Orai1, promoting constitutive Ca2+influx, which is termed store independent Ca2+entry (SICE). The mechanism of SPCA2/Orai1 interaction depends on the N- and C-termini of SPCA2. These extensions may play a dual role in activating not only Orai1, but also Ca2+transport into the Golgi/secretory pathway, which we tested by investigating the impact of various SPCA2 N- and/or C-terminal truncations on SICE and Ca2+transport activity of SPCA2. C-terminal truncations impair SICE and SPCA2 activity, but also affect targeting, whereas N-terminal truncations affect targeting and inactivate SPCA2, but remarkably, SICE activation remains unaffected. Importantly, overexpression of SPCA2 increases the Ca2+content of non-ER stores, which depends on Orai1 and SPCA2 activity. Thus, Orai1-mediated Ca2+-influx and SPCA2-mediated Ca2+uptake activity into the Golgi/secretory pathway might be coupled possibly in a microdomain. This channel/pump complex may efficiently transfer Ca2+into the secretory pathway, which might play a role in SPCA2-expressing secretory cells, such as mammary gland during lactation.
Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Susanne
S
Smaardijk
Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Jialin
J
Chen
Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Frank
F
Wuytack
Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. Electronic address: peter.vangheluwe@kuleuven.be.
Peter
P
Vangheluwe
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007774:Lactation / Q000235:genetics; D000071740:ORAI1 Protein / Q000235:genetics* / Q000378:metabolism; D055571:Secretory Pathway / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C452183:ATP2C2 protein, human; D000252:Calcium-Transporting ATPases; D002118:Calcium
Breast cancer; Ca(2+) Transport; Golgi; Lactation; Orai1; Secretory pathway; Store dependent Ca(2+) entry; Store independent Ca(2+) entry