title: Diverse chemical scaffolds support direct inhibition of the membrane-bound O-acyltransferase porcupine.
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.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Dodge
authors.forename: Jesung
authors.initials: J
authors.lastname: Moon
authors.forename: Rubina
authors.initials: R
authors.lastname: Tuladhar
authors.forename: Jianming
authors.initials: J
authors.lastname: Lu
authors.forename: Leni S
authors.initials: LS
authors.lastname: Jacob
authors.forename: Li-shu
authors.initials: LS
authors.lastname: Zhang
authors.forename: Heping
authors.initials: H
authors.lastname: Shi
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Wang
authors.forename: Enrico
authors.initials: E
authors.lastname: Moro
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mongera
authors.forename: Francesco
authors.initials: F
authors.lastname: Argenton
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Karner
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Carroll
authors.forename: Chuo
authors.initials: C
authors.lastname: Chen
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lum
mesh_terms: D000217:Acyltransferases; D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000494:pharmacology; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology; D002522:Chlorocebus aethiops; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048091:Guided Tissue Regeneration / Q000379:methods*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009924:Organ Culture Techniques; D054457:Tissue Scaffolds; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D051176:beta Catenin; D000217:Acyltransferases; C491188:PORCN protein, human