PUBLICATION

Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages

Authors
Molina, G., Vogt, A., Bakan, A., Dai, W., de Oliveira, P.Q., Znosko, W., Smithgall, T.E., Bahar, I., Lazo, J.S., Day, B.W., and Tsang, M.
ID
ZDB-PUB-090714-6
Date
2009
Source
Nature Chemical Biology   5(9): 680-687 (Journal)
Registered Authors
Molina, Gabriela, Tsang, Michael, Znosko, Wade
Keywords
none
MeSH Terms
  • Allosteric Site
  • Animals
  • Animals, Genetically Modified/metabolism*
  • Cell Lineage*/genetics
  • Cyclohexylamines/chemical synthesis
  • Cyclohexylamines/chemistry
  • Cyclohexylamines/pharmacology*
  • Dual Specificity Phosphatase 6/antagonists & inhibitors*
  • Dual Specificity Phosphatase 6/genetics
  • Enzyme Inhibitors/chemical synthesis
  • Enzyme Inhibitors/chemistry
  • Enzyme Inhibitors/pharmacology*
  • Fibroblast Growth Factors/metabolism
  • Gene Expression Regulation, Developmental/drug effects
  • Heart*/embryology
  • Indenes/chemical synthesis
  • Indenes/chemistry
  • Indenes/pharmacology*
  • Mitogen-Activated Protein Kinase 1/metabolism
  • Protein Binding
  • Small Molecule Libraries
  • Substrate Specificity
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish/metabolism
PubMed
19578332 Full text @ Nat. Chem. Biol.
Abstract
The dual-specificity phosphatase 6 (Dusp6) functions as a feedback regulator of fibroblast growth factor (FGF) signaling to limit the activity of extracellular signal-regulated kinases (ERKs) 1 and 2. We have identified a small-molecule inhibitor of Dusp6-(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI)-using a transgenic zebrafish chemical screen. BCI treatment blocked Dusp6 activity and enhanced FGF target gene expression in zebrafish embryos. Docking simulations predicted an allosteric binding site for BCI within the phosphatase domain. In vitro studies supported a model in which BCI inhibits Dusp6 catalytic activation by ERK2 substrate binding. We used BCI treatment at varying developmental stages to uncover a temporal role for Dusp6 in restricting cardiac progenitors and controlling heart organ size. This study highlights the power of in vivo zebrafish chemical screens to identify new compounds targeting Dusp6, a component of the FGF signaling pathway that has eluded traditional high-throughput in vitro screens.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes