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Title: 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 Luis
Citation: The Journal of Biological Chemistry, 280(33): 29479-29487
Publisher: American Society for Biochemistry and Molecular Biology
Issue Date: 2005
DOI: 10.1074/jbc.M501326200
PubMed ID: 15955804
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Abstract: 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.
Type: Article
Language: en
Keywords: Sarcolemmal calcium Pump
T-cell pathway
Plasma Membrane
ISSN: 0021-9258
Appears in Collections: Molecular Pharmacology Research Group

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