A hidden incoherent switch regulates RCAN1 in the calcineurin-NFAT signaling network

Sung Young Shin, Hee Won Yang, Jeong Rae Kim, Won Do Heo, Kwang Hyun Cho

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37 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)82-90
Number of pages9
JournalJournal of Cell Science
Volume124
Issue number1
DOIs
Publication statusPublished - 1 Jan 2011

Keywords

  • Calcineurin-NFAT signaling pathway
  • Cardiac hypertrophy
  • Incoherent regulation switch
  • Mathematical modeling
  • RCAN1
  • Systems biology

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