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

被引：198

作者：

Molina, Gabriela ^{[1
]}

Vogt, Andreas ^{[2
,3
]}

Bakan, Ahmet ^{[4
]}

Dai, Weixiang ^{[5
]}

de Oliveira, Pierre Queiroz ^{[2
]}

Znosko, Wade ^{[1
]}

Smithgall, Thomas E. ^{[1
,3
]}

Bahar, Ivet ^{[3
,4
]}

Lazo, John S. ^{[2
,3
]}

Day, Billy W. ^{[5
,6
]}

Tsang, Michael ^{[1
]}

机构：

[1] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA

[3] Univ Pittsburgh, Pittsburgh Mol Lib Screening Ctr, Pittsburgh, PA USA

[4] Univ Pittsburgh, Dept Computat Biol, Pittsburgh, PA USA

[5] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA USA

[6] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA

来源：

NATURE CHEMICAL BIOLOGY | 2009年 / 5卷 / 09期

关键词：

CATALYTIC ACTIVATION; CRYSTAL-STRUCTURE; MICROARRAY ANALYSIS; GENETIC ALGORITHM; IN-VIVO; FGF; MAP; PHOSPHATASE; IDENTIFICATION; DOMAIN;

D O I：

10.1038/nchembio.190

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：680 / 687

页数：8

共 51 条

[1] Changes in Sef levels influence auditory brainstem development and function [J].

Abraira, Victoria E. ;

Hyun, Naomi ;

Tucker, Andrew F. ;

Coling, Donald E. ;

Brown, M. Christian ;

Lu, Cindy ;

Hoffman, Gregory R. ;

Goodrich, Lisa V. .

JOURNAL OF NEUROSCIENCE, 2007, 27 (16) :4273-4282

[2]

Almo Steven C., 2007, Journal of Structural and Functional Genomics, V8, P121, DOI 10.1007/s10969-007-9036-1

[3] Anisotropy of fluctuation dynamics of proteins with an elastic network model [J].

Atilgan, AR ;

Durell, SR ;

Jernigan, RL ;

Demirel, MC ;

Keskin, O ;

Bahar, I .

BIOPHYSICAL JOURNAL, 2001, 80 (01) :505-515

[4] Intrinsic dynamics of enzymes in the unbound state and, relation to allosteric regulation [J].

Bahar, Ivet ;

Chennubhotla, Chakra ;

Tobi, Dror .

CURRENT OPINION IN STRUCTURAL BIOLOGY, 2007, 17 (06) :633-640

[5] Toward a Molecular Understanding of the Interaction of Dual Specificity Phosphatases with Substrates: Insights from Structure-Based Modeling and High Throughput Screening [J].

Bakan, Ahmet ;

Lazo, John S. ;

Wipf, Peter ;

Brummond, Kay M. ;

Bahar, Ivet .

CURRENT MEDICINAL CHEMISTRY, 2008, 15 (25) :2536-2544

[6] Transcriptional profiling of endogenous germ layer precursor cells identifies dusp4 as an essential gene in zebrafish endoderm specification [J].

Brown, Jamie L. ;

Snir, Mirit ;

Noushmehr, Houtan ;

Kirby, Martha ;

Hong, Sung-Kook ;

Elkahloun, Abdel G. ;

Feldman, Benjamin .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (34) :12337-12342

[7]

CALLAHAN JF, 1999, Patent No. 9965495

[8] Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase [J].

Camps, M ;

Nichols, A ;

Gillieron, C ;

Antonsson, B ;

Muda, M ;

Chabert, C ;

Boschert, U ;

Arkinstall, S .

SCIENCE, 1998, 280 (5367) :1262-1265

[9] Genetics of heart development [J].

Chen, JN ;

Fishman, MC .

TRENDS IN GENETICS, 2000, 16 (09) :383-388

[10] Discordance between the binding affinity of mitogen-activated protein kinase subfamily members for MAP kinase phosphatase-2 and their ability to activate the phosphatase catalytically [J].

Chen, PL ;

Hutter, D ;

Yang, XL ;

Gorospe, M ;

Davis, RJ ;

Liu, YS .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (31) :29440-29449

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