A Cell Active Chemical GEF Inhibitor Selectively Targets the Trio/RhoG/Rac1 Signaling Pathway

被引：81

作者：

Bouquier, Nathalie ^{[1
,2
]}

Vignal, Emmanuel ^{[1
,2
]}

Charrasse, Sophie ^{[1
,2
]}

Weill, Mylene ^{[3
]}

Schmidt, Susanne ^{[1
,2
]}

Leonetti, Jean-Paul ^{[4
,5
]}

Blangy, Anne ^{[1
,2
]}

Fort, Philippe ^{[1
,2
]}

机构：

[1] Univ Montpellier I, Ctr Rech Biochim Macromol, CNRS, F-34293 Montpellier, France

[2] Univ Montpellier 2, Ctr Rech Biochim Macromol, CNRS, F-34293 Montpellier, France

[3] Univ Montpellier 2, CNRS, Inst Sci Evolut, F-34293 Montpellier, France

[4] Univ Montpellier I, Ctr Etud Agents Pathogenes & Biotechnol Sante, CNRS, F-34965 Montpellier, France

[5] Univ Montpellier 2, Ctr Etud Agents Pathogenes & Biotechnol Sante, CNRS, F-34965 Montpellier, France

来源：

CHEMISTRY & BIOLOGY | 2009年 / 16卷 / 06期

关键词：

NUCLEOTIDE-EXCHANGE-FACTOR; SMALL-MOLECULE INHIBITOR; RHO-GTPASES; THERAPEUTIC TARGETS; MYOBLAST FUSION; PROTEIN-KINASE; TRIO; RAC; ACTIVATION; IDENTIFICATION;

D O I：

10.1016/j.chembiol.2009.04.012

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：

RhoGEFs (guanine nucleotide exchange factors of the Rho GTPase family) are upstream regulators of cell adhesion and migration pathways, thus representing attractive yet relatively unexplored targets for the development of anti-invasive drugs. We screened for chemical inhibitors of TrioN, the N-terminal GEF domain of the multidomain Trio protein, and identified ITX3 as a nontoxic inhibitor. In transfected mammalian cells, ITX3 blocked TrioN-mediated dorsal membrane ruffling and Rac1 activation while having no effect on GEF337-, Tiam1-, or Vav2-mediated RhoA or Rac1 activation. ITX3 specifically inhibited endogenous TrioN activity, as evidenced by its ability to inhibit neurite outgrowth in nerve growth factor (NGF)-stimulated PC12 cells or C2C12 differentiation into myotubes. This study introduces a selective cell active inhibitor of the Trio/RhoG/Rac1 pathway and validates RhoGEFs as druggable targets.

引用

页码：657 / 666

页数：10

共 52 条

[51] Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1 [J].