Diverse chemical scaffolds support direct inhibition of the membrane-bound O-acyltransferase porcupine

Michael E. Dodge, Jesung Moon, Rubina Tuladhar, Jianming Lu, Leni S. Jacob, Li Shu Zhang, Heping Shi, Xiaolei Wang, Enrico Moro, Alessandro Mongera, Francesco Argenton, Courtney M. Karner, Thomas J. Carroll, Chuo Chen, James F. Amatruda, Lawrence Lum

Research output: Contribution to journalArticle

54 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)23246-23254
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number27
DOIs
StatePublished - Jun 29 2012

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Porcupines
Wnt Proteins
Acyltransferases
Catenins
Scaffolds
Membranes
Vertebrates
Genes
Tankyrases
Molecules
Glycogen Synthase Kinase 3
Tissue homeostasis
Acylation
Zebrafish
Transducers
Dissection
Chemical compounds
Embryonic Development
Catalytic Domain
Homeostasis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Diverse chemical scaffolds support direct inhibition of the membrane-bound O-acyltransferase porcupine. / Dodge, Michael E.; Moon, Jesung; Tuladhar, Rubina; Lu, Jianming; Jacob, Leni S.; Zhang, Li Shu; Shi, Heping; Wang, Xiaolei; Moro, Enrico; Mongera, Alessandro; Argenton, Francesco; Karner, Courtney M.; Carroll, Thomas J.; Chen, Chuo; Amatruda, James F.; Lum, Lawrence.

In: Journal of Biological Chemistry, Vol. 287, No. 27, 29.06.2012, p. 23246-23254.

Research output: Contribution to journalArticle

Dodge, ME, Moon, J, Tuladhar, R, Lu, J, Jacob, LS, Zhang, LS, Shi, H, Wang, X, Moro, E, Mongera, A, Argenton, F, Karner, CM, Carroll, TJ, Chen, C, Amatruda, JF & Lum, L 2012, 'Diverse chemical scaffolds support direct inhibition of the membrane-bound O-acyltransferase porcupine', Journal of Biological Chemistry, vol. 287, no. 27, pp. 23246-23254. https://doi.org/10.1074/jbc.M112.372029
Dodge, Michael E. ; Moon, Jesung ; Tuladhar, Rubina ; Lu, Jianming ; Jacob, Leni S. ; Zhang, Li Shu ; Shi, Heping ; Wang, Xiaolei ; Moro, Enrico ; Mongera, Alessandro ; Argenton, Francesco ; Karner, Courtney M. ; Carroll, Thomas J. ; Chen, Chuo ; Amatruda, James F. ; Lum, Lawrence. / Diverse chemical scaffolds support direct inhibition of the membrane-bound O-acyltransferase porcupine. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 27. pp. 23246-23254.
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