Protein kinase CK2-dependent phosphorylation of the human Regulators of Calcineurin reveals a novel mechanism regulating the calcineurin-NFATc signaling pathway.
Biochim Biophys Acta
; 1833(10): 2311-21, 2013 Oct.
Article
en En
| MEDLINE
| ID: mdl-23732701
ABSTRACT
Cyclosporine A and FK506 produce immunosuppression by blocking calcineurin phosphatase activity and consequently activation of cytosolic Nuclear Factor of Activated T-cell (NFATc) transcription factor. Due to the chronic toxicity associated with their administration, the development of more specific immunosuppressants is currently an important unmet medical need. In this context, an immunosuppressant peptide derived from the CIC motif of the human Regulators of Calcineurin (RCAN) proteins has been shown to inhibit NFATc signaling without affecting general phosphatase activity of calcineurin. Here we show that protein kinase CK2 phosphorylates a conserved serine residue within the CIC motif of vertebrate RCANs, which increases its affinity for calcineurin and consequently its inhibition of NFATc-dependent gene expression in activated T-cells. Molecular modeling studies have led us to identify a positively charged interaction site on the surface of calcineurin where the phosphorylated serine residue of the CIC motif would normally locate. Finally, we have also identified RCAN3 as a new phosphoprotein with multiple phosphorylation sites. Therefore, our findings reveal for the first time a novel molecular mechanism underlying the regulation of calcineurin-NFATc signaling by means of phosphorylation of the CIC motif of RCAN proteins. The knowledge of how RCAN proteins modulate the calcineurin-NFATc pathway paves the way for the development of potent novel selective immunosuppressant drugs.
Palabras clave
CIC sequence; CK2; CalcineurinNFATc signaling; Cn; CnA; CsA; Immunosuppression; Io; Ionomycin; NFATc; PMA; PXIXIT; Phorbol 12-miristate 13-acetate; Phosphorylation; RCAN; RCAN (formerly calcipressin) inhibitor of calcineurin sequence; Regulators of Calcineurin; calcineurin; calcineurin catalytic subunit A; cyclosporin A; cytosolic Nuclear Factor of Activated T-cells; protein kinase CK2
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Regulación de la Expresión Génica
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Calcineurina
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Quinasa de la Caseína II
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Péptidos y Proteínas de Señalización Intracelular
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Factores de Transcripción NFATC
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Proteínas Musculares
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Biochim Biophys Acta
Año:
2013
Tipo del documento:
Article
País de afiliación:
España