Regulation of RCAN1 Protein Activity by Dyrk1A Protein-mediated Phosphorylation
| Autor: | Song-Hee Yoon, Jung-Hwa Park, Sun-Hee Choi, Min-Su Jung, Ji Youn Oh, Young Shin Ryu, Woo-Joo Song, Mi-Yang Kwen, Sul-Hee Chung |
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| Rok vydání: | 2011 |
| Předmět: |
Transcription
Genetic DYRK1A Chromosomes Human Pair 21 Phosphatase Muscle Proteins Mice Transgenic tau Proteins Protein Serine-Threonine Kinases Biology Biochemistry Glycogen Synthase Kinase 3 Mice GSK-3 Animals Humans Phosphorylation Molecular Biology Glycogen Synthase Kinase 3 beta NFATC Transcription Factors Kinase Calcineurin Calcium-Binding Proteins Intracellular Signaling Peptides and Proteins Molecular Bases of Disease NFAT Cell Biology Protein-Tyrosine Kinases Molecular biology DNA-Binding Proteins HEK293 Cells Down Syndrome Signal transduction Protein Binding Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 286:40401-40412 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m111.253971 |
| Popis: | Two genes on chromosome 21, namely dual specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) and regulator of calcineurin 1 (RCAN1), have been implicated in some of the phenotypic characteristics of Down syndrome, including the early onset of Alzheimer disease. Although a link between Dyrk1A and RCAN1 and the nuclear factor of activated T cells (NFAT) pathway has been reported, it remains unclear whether Dyrk1A directly interacts with RCAN1. In the present study, Dyrk1A is shown to directly interact with and phosphorylate RCAN1 at Ser(112) and Thr(192) residues. Dyrk1A-mediated phosphorylation of RCAN1 at Ser(112) primes the protein for the GSK3β-mediated phosphorylation of Ser(108). Phosphorylation of RCAN1 at Thr(192) by Dyrk1A enhances the ability of RCAN1 to inhibit the phosphatase activity of calcineurin (Caln), leading to reduced NFAT transcriptional activity and enhanced Tau phosphorylation. These effects are mediated by the enhanced binding of RCAN1 to Caln and its extended half-life caused by Dyrk1A-mediated phosphorylation. Furthermore, an increased expression of phospho-Thr(192)-RCAN1 was observed in the brains of transgenic mice overexpressing the Dyrk1A protein. These results suggest a direct link between Dyrk1A and RCAN1 in the Caln-NFAT signaling and Tau hyperphosphorylation pathways, supporting the notion that the synergistic interaction between the chromosome 21 genes RCAN1 and Dyrk1A is associated with a variety of pathological features associated with DS. |
| Databáze: | OpenAIRE |
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