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Functional regulation of Wnt protein through post-translational modifications
Jia Yu1, David M Virshup1,2
1Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 Singapore.
Biochemical Society Transactions
|December 9, 2022
Summary
Wnt signaling is regulated by essential post-translational modifications, including O-linked palmitoleation catalyzed by Porcupine (PORCN), which is crucial for Wnt protein function and interactions. These modifications control Wnt activity at multiple levels, impacting development and homeostasis.
Area of Science:
- Cell Biology
- Molecular Biology
- Developmental Biology
Background:
- Wnts are lipid-modified signaling glycoproteins vital for metazoan development and homeostasis.
- Their function is critically dependent on post-translational modifications, including a unique O-linked palmitoleation.
- This modification is essential for Wnt binding to its transporter Wntless (WLS) and receptor Frizzled (FZD).
Purpose of the Study:
- To elucidate the regulatory mechanisms controlling Wnt signaling.
- To highlight the critical role of post-translational modifications in Wnt protein function.
- To provide an overview of the multi-layered control of Wnt activity.
Main Methods:
- Review of recent structural and functional studies on Wnt modifications.
- Analysis of Wnt biosynthesis, trafficking, and degradation pathways.
- Examination of enzymatic modifications and their impact on Wnt activity.
Main Results:
- O-linked palmitoleation by Porcupine (PORCN) in the ER is essential for Wnt function.
- Wntless (WLS) abundance is regulated by intracellular recycling and degradation.
- Glycosylation, disulfide bond formation, N-terminal cleavage by TIKI, and de-palmitoleation by NOTUM further modulate Wnt activity.
Conclusions:
- Wnt signaling is precisely controlled through a complex network of post-translational modifications.
- These modifications occur at various stages, from biosynthesis to extracellular interactions.
- Understanding these modifications is key to comprehending Wnt-mediated biological processes.
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