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Targeted inhibition of the Shroom3-Rho kinase protein-protein interaction circumvents Nogo66 to promote axon outgrowth.

BMC neuroscience | Jun 16, 2015

BACKGROUND: Inhibitory molecules in the adult central nervous system, including NogoA, impede neural repair by blocking axon outgrowth. The actin-myosin regulatory protein Shroom3 directly interacts with Rho kinase and conveys axon outgrowth inhibitory signals from Nogo66, a C-terminal inhibitory domain of NogoA. The purpose of this study was to identify small molecules that block the Shroom3-Rho kinase protein-protein interaction as a means to modulate NogoA signaling and, in the longer term, enhance axon outgrowth during neural repair. RESULTS: A high throughput screen for inhibitors of the Shroom3-Rho kinase protein-protein interaction identified CCG-17444 (Chem ID: 2816053). CCG-17444 inhibits the Shroom3-Rho kinase interaction in vitro with micromolar potency. This compound acts through an irreversible, covalent mechanism of action, targeting Shroom3 Cys1816 to inhibit the Shroom3-Rho kinase protein-protein interaction. Inhibition of the Shroom3-Rho kinase protein-protein interaction with CCG-17444 counteracts the inhibitory action of Nogo66 and enhances neurite outgrowth. CONCLUSIONS: This study identifies a small molecule inhibitor of the Shroom3-Rho kinase protein-protein interaction that circumvents the inhibitory action of Nogo66 in neurons. Identification of a small molecule compound that blocks the Shroom3-Rho kinase protein-protein interaction provides a first step towards a potential new strategy for enhancing neural repair.

Pubmed ID: 26077244 RIS Download

Mesh terms: Animals | Axons | Cell Enlargement | Cell Line, Tumor | Cells, Cultured | Cerebellum | Dose-Response Relationship, Drug | Escherichia coli | High-Throughput Screening Assays | Mice | Microfilament Proteins | Myelin Proteins | Nogo Proteins | Protein Kinase Inhibitors | Pyrimidinones | Quinolones | Recombinant Proteins | rho-Associated Kinases

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Associated grants

  • Agency: NCATS NIH HHS, Id: UL1 TR000433
  • Agency: NIGMS NIH HHS, Id: T32 GM008353
  • Agency: NCI NIH HHS, Id: P30 CA046592
  • Agency: NCATS NIH HHS, Id: UL1TR000433
  • Agency: NIA NIH HHS, Id: R21 AG034264
  • Agency: NIDDK NIH HHS, Id: P30 DK020572
  • Agency: NIA NIH HHS, Id: R21AG034264

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Integrated Animals is a virtual database currently indexing available animal strains and mutants from: AGSC (Ambystoma), BCBC (mice), BDSC (flies), CWRU Cystic Fibrosis Mouse Models (mice), DGGR (flies), FlyBase (flies), IMSR (mice), MGI (mice), MMRRC (mice), NSRRC (pig), NXR (Xenopus), RGD (rats), Sperm Stem Cell Libraries for Biological Research (rats), Tetrahymena Stock Center (Tetrahymena), WormBase (worms), XGSC (Xiphophorus), ZFIN (zebrafish), and ZIRC (zebrafish).

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