Notum is required for neural and head induction via Wnt deacylation, oxidation and inactivation

By Xinjun Zhang, Seong-Moon Cheong, Nathalia Amado, Alice H. Reis, Bryan T. MacDonald, M. Zebisch, E. Jones, J. Abreu, Xi He. 2015

174 citations recorded by the source corpus.

Summary Secreted Wnt morphogens are essential for embryogenesis and homeostasis, and require a lipid/palmitoleoylate modification for receptor binding and activity. Notum is a secreted Wnt antagonist that belongs to the α/β hydrolase superfamily, but its mechanism of action and roles in vertebrate embryogenesis are not fully understood. Here we report that Notum hydrolyzes the Wnt palmitoleoylate adduct extracellularly, resulting in inactivated Wnt proteins that form oxidized oligomers incapable of receptor binding. Thus Notum is a Wnt deacylase, and palmitoleoylation is obligatory for the Wnt structure that maintains its active monomeric conformation. Notum is expressed in naïve ectoderm and neural plate in Xenopus and is required for neural and head induction. These findings suggest that distinct mechanisms of Wnt inactivation by the Tiki protease in the Organizer and the Notum deacylase in presumptive neuroectoderm orchestrate vertebrate brain development.

Subfields: Genetics, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Hans Clevers
2. R. Nusse
3. S. Angers
4. Z. Steinhart
5. Pengfei Lu

In Molecular Biology

1. Hans Clevers
2. R. Nusse
3. S. Angers
4. Z. Steinhart
5. Paul V. Fish
6. Elaine Fuchs
7. C. Blanpain
8. Xi He

Citations in the corpus

• Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity (2023, background): “Carboxylesterase Notum is a serine hydrolase enzyme that catalyses the delipidation of Wnt proteins and so regulates Wnt signalling [1,2].”
• Single-Cell Profiling and SCOPE-Seq Reveal Lineage Dynamics of Adult Ventricular-Subventricular Zone Neurogenesis and NOTUM as a Key Regulator (2020, unknown): “As a secreted WNT antagonist, NOTUM is active in the extracellular space (Zhang et al., 2015), it but can also be retained at the cell surface via binding to glycosaminoglycans on glypicans (Kakugawa et al., 2015).”
• Selective Irreversible Inhibitors of the Wnt-Deacylating Enzyme NOTUM Developed by Activity-Based Protein Profiling (2018, unknown): “10,11 NOTUM expression is itself regulated by Wnt signaling and may serve as a biomarker for Wnt-dependent cancers that are sensitive to PORCN inhibitors.”
• Wnt signaling in development and tissue homeostasis (2018, background): “At the ligand level, the extracellular enzymes Tiki and Notum function as a protease and a carboxylesterase to cleave the N terminus of Wnts (Zhang et al., 2012) or remove their palmitoleate moiety (Kakugawa et al., 2015; Zhang et al., 2015), respectively.”
• Wnt/ b -Catenin Signaling, Disease, and Emerging Therapeutic Modalities (2017, background): “A recent example is Notum, originally discovered in Drosophila as an enzyme, a carboxylesterase that can remove the palmitoleate modification on Wnt (Kakugawa et al., 2015; Zhang et al., 2015) (Figure 1).”