Dodge, M.E., Moon, J., Tuladhar, R., Lu, J., Jacob, L.S., Zhang, L.S., Shi, H., Wang, X., Moro, E., Mongera, A., Argenton, F., Karner, C.M., Carroll, T.J., Chen, C., Amatruda, J.F., and Lum, L. (2012) Diverse Chemical Scaffolds Support Direct Inhibition of the Membrane-bound O-Acyltransferase Porcupine. The Journal of biological chemistry. 287(27):23246-23254.
ABSTRACT
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.
