title: A hidden incoherent switch regulates RCAN1 in the calcineurin-NFAT signaling network.
abstract: Regulator of calcineurin 1 (RCAN1) is a key regulator of the calcineurin-NFAT signaling network in organisms ranging from yeast to human, but its functional role is still under debate because different roles of RCAN1 have been suggested under various experimental conditions. To elucidate the mechanisms underlying the RCAN1 regulatory system, we used a systems approach by combining single-cell experimentation with in silico simulations. In particular, we found that the nuclear export of GSK3β, which switches on the facilitative role of RCAN1 in the calcineurin-NFAT signaling pathway, is promoted by PI3K signaling. Based on this, along with integrated information from previous experiments, we developed a mathematical model in which the functional role of RCAN1 changes in a dose-dependent manner: RCAN1 functions as an inhibitor when its levels are low, but as a facilitator when its levels are high. Furthermore, we identified a hidden incoherent regulation switch that mediates this role change, which entails negative regulation through RCAN1 binding to calcineurin and positive regulation through sequential phosphorylation of RCAN1.
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Sung-Young
authors.initials: SY
authors.lastname: Shin
authors.forename: Hee Won
authors.initials: HW
authors.lastname: Yang
authors.forename: Jeong-Rae
authors.initials: JR
authors.lastname: Kim
authors.forename: Won Do
authors.initials: WD
authors.lastname: Heo
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Cho
mesh_terms: D021581:Active Transport, Cell Nucleus; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D019703:Calcineurin; 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; D019869:Phosphatidylinositol 3-Kinases; C108612:RCAN1 protein, human; C000605506:GSK3B protein, human