Regulation of RCAN1 Protein Activity by Dyrk1A Protein-mediated Phosphorylation

• Published in: The Journal of biological chemistry 2011-11, Vol.286 (46), p.40401-40412
• Main Authors: Jung, Min-Su, Park, Jung-Hwa, Ryu, Young Shin, Choi, Sun-Hee, Yoon, Song-Hee, Kwen, Mi-Yang, Oh, Ji Youn, Song, Woo-Joo, Chung, Sul-Hee
• Format: Article
• Language: English
• Subjects: Animals; Calcineurin; Calcineurin - genetics; Calcineurin - metabolism; Calcium-Binding Proteins; Chromosomes, Human, Pair 21 - genetics; Chromosomes, Human, Pair 21 - metabolism; DNA-Binding Proteins; Down Syndrome; Down Syndrome - genetics; Down Syndrome - metabolism; Dual Specificity Kinase; Dyrk Kinases; Dyrk1A; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Mice; Mice, Transgenic; Molecular Bases of Disease; Muscle Proteins - genetics; Muscle Proteins - metabolism; Neurological Diseases; NFAT Transcription Factor; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Phosphorylation; Phosphorylation - genetics; Protein Binding - genetics; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; RCAN1; Signal Transduction - genetics; tau Proteins - genetics; tau Proteins - metabolism; Transcription, Genetic - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.253971

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 Ser112 and Thr192 residues. Dyrk1A-mediated phosphorylation of RCAN1 at Ser112 primes the protein for the GSK3β-mediated phosphorylation of Ser108. Phosphorylation of RCAN1 at Thr192 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-Thr192-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.