Diverse Chemical Scaffolds Support Direct Inhibition of the Membrane-bound O -Acyltransferase Porcupine

Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2012; 287(27):23246-54. DOI: 10.1074/jbc.M112.372029
Source: PubMed


Secreted Wnt proteins constitute one of the largest families of intercellular signaling molecules in vertebrates with essential
roles in embryonic development and adult tissue homeostasis. The functional redundancy of Wnt genes and the many forms of
cellular responses they elicit, including some utilizing the transcriptional co-activator β-catenin, has limited the ability
of classical genetic strategies to uncover their roles in vivo. We had previously identified a chemical compound class termed Inhibitor of Wnt Production (or IWP) that targets Porcupine
(Porcn), an acyltransferase catalyzing the addition of fatty acid adducts onto Wnt proteins. Here we demonstrate that diverse
chemical structures are able to inhibit Porcn by targeting its putative active site. When deployed in concert with small molecules
that modulate the activity of Tankyrase enzymes and glycogen synthase kinase 3 β (GSK3β), additional transducers of Wnt/β-catenin
signaling, the IWP compounds reveal an essential role for Wnt protein fatty acylation in eliciting β-catenin-dependent and
-independent forms of Wnt signaling during zebrafish development. This collection of small molecules facilitates rapid dissection
of Wnt gene function in vivo by limiting the influence of redundant Wnt gene functions on phenotypic outcomes and enables temporal manipulation of Wnt-mediated
signaling in vertebrates.

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Available from: Heping Shi, Sep 07, 2015
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    • "Attempts to pharmacologically inhibit WNT signaling have lead to the identification of a number of small molecules that act at different levels in the core signaling cascade (e.g., Lepourcelet et al, 2004; Curtin & Lorenzi, 2010; Anastas & Moon, 2013; see These include inhibitors of Porcupine and Tankyrases, which promote normal WNT ligand secretion or cytoplasmic transduction, respectively (Huang et al, 2009; Dodge et al, 2012; Waaler et al, 2012; Lau et al, 2013). However, activation of WNT signaling below the level of ligand function or cytoplasmic transduction, as in the case of loss of APC for instance (see above), would appear to complicate the effects of pathway blockade at upstream levels. "
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    • "To investigate the role of PPN as a Wnt palmitoyltransferase in gastric cancer, we used a palmitoyltransferase inhibitor (IWP-2) specific for PPN activity (10,11). Following treatment in the MKN28 cell line for four days, 10–50 μM IWP-2 significantly suppressed the proliferation of MKN28 cells (P<0.05; "
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