Journal ArticleDOI
Identification of a specific inhibitor of the Dishevelled PDZ domain
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This compound provides a basis for rational design of high-affinity inhibitors of the PDZ domain, which can block Wnt signaling by interrupting the Fz-Dvl interaction.Abstract:
The Wnt signaling pathways are involved in embryo development as well as in tumorigenesis. Dishevelled (Dvl) transduces Wnt signals from the receptor Frizzled (Fz) to downstream components in canonical and noncanonical Wnt signaling pathways. The Dvl PDZ domain is thought to play an essential role in both pathways, and we recently demonstrated that the Dvl PDZ domain binds directly to Fz receptors. In this study, using structure-based virtual ligand screening, we identified an organic molecule (NSC668036) from the National Cancer Institute small-molecule library that can bind to the Dvl PDZ domain. We then used molecular dynamics simulation to analyze the binding between the PDZ domain and NSC668036 in detail. In addition, we showed that, in Xenopus, as expected, NSC668036 inhibited the signaling induced by Wnt3A. This compound provides a basis for rational design of high-affinity inhibitors of the PDZ domain, which can block Wnt signaling by interrupting the Fz-Dvl interaction.read more
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Book ChapterDOI
Role of PDZ proteins in regulating trafficking, signaling, and function of GPCRs: means, motif, and opportunity.
TL;DR: PDZ proteins may impact receptor signaling by diverse mechanisms that include retaining the receptor at the cell membrane, thereby increasing the duration of ligand binding, as well as importantly influencing GPCR internalization, trafficking, recycling, and intracellular sorting.
Journal ArticleDOI
The WNT signaling pathway from ligand secretion to gene transcription: Molecular mechanisms and pharmacological targets
TL;DR: The complexity of WNT signal transduction is described starting from the processes involved in W NT ligand biogenesis and secretion by WNT producing cells followed by a comprehensive overview of the molecular signaling events ultimately resulting in enhanced transcription of specific genes in WNT receiving cells.
Journal ArticleDOI
Inhibition of Wnt signaling by Dishevelled PDZ peptides
Yingnan Zhang,Brent A. Appleton,Brent A. Appleton,Christian Wiesmann,Ted Lau,Mike Costa,Rami N. Hannoush,Sachdev S. Sidhu,Sachdev S. Sidhu +8 more
TL;DR: It is found that the binding cleft of the Dishevelled PDZ domain is more flexible than those of canonical PDZ domains and enables recognition of both C-terminal and internal peptides.
Journal ArticleDOI
Small-molecule synergist of the Wnt/β-catenin signaling pathway
Qisheng Zhang,Michael B. Major,Shinichi Takanashi,Nathan D. Camp,Naoyuki Nishiya,Eric C. Peters,Mark H. Ginsberg,Xiaoying Jian,Xiaoying Jian,Paul A. Randazzo,Peter G. Schultz,Peter G. Schultz,Randall T. Moon,Sheng Ding +13 more
TL;DR: A purine derivative, QS11, is discovered that synergizes with Wnt-3a ligand in the activation of Wnt/β-catenin signal transduction and binds and inhibits the GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1), suggesting that QS 11 modulates Wnt /β- catenin signaling through an effect on protein trafficking.
Journal ArticleDOI
Targeting self-renewal pathways in cancer stem cells: clinical implications for cancer therapy.
TL;DR: It is hopeful that the SRPs in CSCs offer a promising target to alter their survival strategies and impede their tumorigenic potential, but there are many perils associated with the direct targeting method by conventional therapeutic agents such as off targets, poor bioavailability and poor cellular distribution.
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