Phosphorylation of calcipressin 1 increases its ability to inhibit calcineurin and decreases calcipressin half-life.
Calcipressin 1 is an endogenous inhibitor of calcineurin, which is a serine/threonine phosphatase under the control of Ca(2+) and calmodulin. Calcipressin 1 is encoded by DSCR1, a gene on human chromosome 21 with seven exons, exons 1-4 are alternative first exons (isoforms 1-4). We show that calcipressin 1 isoform 1 has an N-terminal coding region longer than that previously described, and this generates a new polypeptide of 252 amino acids. This polypeptide is able to interact with calcineurin A and to inhibit NF-AT-mediated transcriptional activation. We demonstrate for the first time that endogenous calcipressin 1 exists as a complex together with the calcineurin A and B heterodimer. Calcipressin 1 is a phosphoprotein that increases its capacity to inhibit calcineurin when phosphorylated at the FLISPP motif, and this phosphorylation also controls the half-life of calcipressin 1 by accelerating its degradation. Additionally, we have also detected further phosphorylation sites outside the FLISPP motif and these contribute to the complex phosphorylation pattern of calcipressin 1. Taking all these results into consideration we suggest that phosphorylation of calcipressin 1 is involved in the regulation of the phosphatase activity of calcineurin and can therefore act as a modulator of calcineurin-dependent cellular pathways.
Genescà
Lali
L
Genes and Disease Program, Centre de Regulació Genòmica-CRG, Passeig Marítim 37-49, 08003-Barcelona, Spain.
Aubareda
Anna
A
Fuentes
Juan J
JJ
Estivill
Xavier
X
De La Luna
Susana
S
Pérez-Riba
Mercè
M
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002522:Chlorocebus aethiops; D003062:Codon / Q000235:genetics; D006224:Cricetinae; D004268:DNA-Binding Proteins; D005091:Exons / Q000235:genetics; D006388:Hemagglutinins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009124:Muscle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D014162:Transfection; D014407:Tumor Cells, Cultured
D065095:Calcineurin Inhibitors; D003062:Codon; D004268:DNA-Binding Proteins; D006388:Hemagglutinins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D019703:Calcineurin