The sarcolemmal calcium pump inhibits the calcineurin/nuclear factor of activated T-cell pathway via interaction with the calcineurin A catalytic subunit
Authors
Buch, Mamta H.Pickard, Adam
Rodriguez, Antonio
Gillies, Sheona
Maass, Alexander H.
Emerson, Michael
Cartwright, Elizabeth J.
Williams, Judith C.
Oceandy, Delvac
Redondo, Juan Miguel
Neyses, Ludwig
Armesilla, Angel
Issue Date
2005
Metadata
Show full item recordAbstract
The calcineurin/nuclear factor of activated T-cell (NFAT) pathway represents a crucial transducer of cellular function. There is increasing evidence placing the sarcolemmal calcium pump, or plasma membrane calcium/calmodulin ATPase pump (PMCA), as a potential modulator of signal transduction pathways. We demonstrate a novel interaction between PMCA and the calcium/calmodulin-dependent phosphatase, calcineurin, in mammalian cells. The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. Endogenous calcineurin activity, assessed by measuring the transcriptional activity of its best characterized substrate, NFAT, was significantly inhibited by 60% in the presence of ectopic PMCA4b. This inhibition was notably reversed by the co-expression of the PMCA4b interaction domain, demonstrating the functional significance of this interaction. PMCA4b was, however, unable to confer its inhibitory effect in the presence of a calcium/calmodulin-independent constitutively active mutant calcineurin A suggesting a calcium/calmodulin-dependent mechanism. The modulatory function of PMCA4b is further supported by the observation that endogenous calcineurin moves from the cytoplasm to the plasma membrane when PMCA4b is overexpressed. We suggest recruitment by PMCA4b of calcineurin to a low calcium environment as a possible explanation for these findings. In summary, our results offer strong evidence for a novel functional interaction between PMCA and calcineurin, suggesting a role for PMCA as a negative modulator of calcineurin-mediated signaling pathways in mammalian cells. This study reinforces the emerging role of PMCA as a molecular organizer and regulator of signaling transduction pathways.Citation
Buch, M., Pickard, A., Rodriguez, A. et al. (2005) The Sarcolemmal Calcium Pump Inhibits the Calcineurin/Nuclear Factor of Activated T-cell Pathway via Interaction with the Calcineurin A Catalytic Subunit. Journal of Biological Chemistry, 280(33), pp. 29479-29487.PubMed ID
15955804Additional Links
http://www.jbc.org/cgi/reprint/280/33/29479Type
Journal articleLanguage
enISSN
0021-9258ae974a485f413a2113503eed53cd6c53
10.1074/jbc.M501326200
Scopus Count
Collections
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0/