title: Regulation of RCAN1 protein activity by Dyrk1A protein-mediated phosphorylation.
abstract: 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.
authors.affiliation: Graduate Program in Neuroscience, Institute for Brain Science and Technology, FIRST Research Group, Inje University, 633-146 Gaegeum-2-Dong, Busanjin-Gu, Busan 614-735, South Korea.
authors.forename: Min-Su
authors.initials: MS
authors.lastname: Jung
authors.forename: Jung-Hwa
authors.initials: JH
authors.lastname: Park
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Ryu
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Choi
authors.forename: Song-Hee
authors.initials: SH
authors.lastname: Yoon
authors.forename: Mi-Yang
authors.initials: MY
authors.lastname: Kwen
authors.forename: Ji Youn
authors.initials: JY
authors.lastname: Oh
authors.forename: Woo-Joo
authors.initials: WJ
authors.lastname: Song
authors.forename: Sul-Hee
authors.initials: SH
authors.lastname: Chung
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D019703:Calcineurin; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016875:tau Proteins; D000097603:Dyrk Kinases; C511512:DSCR1 protein, mouse; C054369:MAPT protein, human; C108612:RCAN1 protein, human; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse