title: Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages.
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.
authors: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors: Gabriela
authors: G
authors: Molina
authors: Andreas
authors: A
authors: Vogt
authors: Ahmet
authors: A
authors: Bakan
authors: Weixiang
authors: W
authors: Dai
authors: Pierre
authors: P
authors: Queiroz de Oliveira
authors: Wade
authors: W
authors: Znosko
authors: Thomas E
authors: TE
authors: Smithgall
authors: Ivet
authors: I
authors: Bahar
authors: John S
authors: JS
authors: Lazo
authors: Billy W
authors: BW
authors: Day
authors: Michael
authors: M
authors: Tsang
mesh_terms: D000495:Allosteric Site; D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism*; D019070:Cell Lineage / Q000235:genetics; D003514:Cyclohexylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054642:Dual Specificity Phosphatase 6 / Q000037:antagonists & inhibitors* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006321:Heart / Q000196:embryology; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D011485:Protein Binding; D054852:Small Molecule Libraries; D013379:Substrate Specificity; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000378:metabolism
chemical_list: C543522:2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one; D003514:Cyclohexylamines; D004791:Enzyme Inhibitors; D007192:Indenes; D054852:Small Molecule Libraries; D005346:Fibroblast Growth Factors; D019950:Mitogen-Activated Protein Kinase 1; D054642:Dual Specificity Phosphatase 6