کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10802281 | 1055679 | 2013 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Protein kinase CK2-dependent phosphorylation of the human Regulators of Calcineurin reveals a novel mechanism regulating the calcineurin-NFATc signaling pathway
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1833, Issue 10, October 2013, Pages 2311-2321
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1833, Issue 10, October 2013, Pages 2311-2321
نویسندگان
Sergio MartÃnez-Høyer, Álvaro Aranguren-Ibáñez, Javier GarcÃa-GarcÃa, Eva Serrano-Candelas, Jordi Vilardell, Virginia Nunes, Fernando Aguado, Baldo Oliva, Emilio Itarte, Mercè Pérez-Riba,