Reversible acetylation modulates dishevelled-2 puncta formation in canonical Wnt signaling activation

Signal Transduction and Targeted Therapy, 2020 · DOI: https://doi.org/10.1038/s41392-020-00229-0 · Published: June 15, 2020

Oncology Genetics

Simple Explanation

Dishevelled-2 (DVL2) is a key protein in the Wnt signaling pathway, which is important for cell development and growth. This study found that a modification called acetylation, specifically at a site called K68 on DVL2, affects how DVL2 clumps together to form signaling hubs. The researchers discovered that an enzyme called CBP adds this acetyl group to DVL2, promoting the formation of these DVL2 clumps. Conversely, another enzyme called SIRT2 removes the acetyl group, causing the clumps to break apart. In colorectal cancer cells, they observed that DVL2 with the acetyl group was more common in tumor tissues, suggesting that this modification plays a role in cancer development. This suggests DVL2 acetylation may serve as a therapeutic target in clinical treatment of CRCs.

Study Duration

Not specified

Participants

CRC patients

Evidence Level

Not specified

Key Findings

1
CBP-dependent acetylation of DVL2 at K68 promotes DVL2 signalosome formation.
2
SIRT2 deacetylates DVL2, attenuating DVL2 homo-polymerization via deacetylation on K68.
3
Acetylation at DVL2-K68 is required for full activation of Wnt signaling by DVL2, influencing β-catenin activity and target gene expression.

Research Summary

This letter identifies CBP-dependent DVL2 acetylation at K68 as a novel regulator in Wnt3a-induced DVL signalosome formation. DVL2-K68 acetylation is critical for activation of downstream β-catenin signaling. DVL2-K68 acetylation may serve as a potential therapeutic target in clinical treatment of CRCs.

Practical Implications

Therapeutic Target

DVL2-K68 acetylation may represent a novel therapeutic target for the treatment of colorectal cancers.

Wnt Signaling Regulation

Understanding the reversible acetylation of DVL2 provides insights into the regulation of canonical Wnt signaling.

CRC Development

High levels of DVL2-aK68 in some CRCs may result from reduction of SIRT2, which acts as a tumor suppressor.

Study Limitations

1
The exact mechanisms of SIRT2 recruitment to DVL2 signalosomes need further investigation.
2
The study focuses primarily on in vitro and cell-based assays; further in vivo studies are needed.
3
The study only explores DVL2 acetylation in the context of colorectal cancer; the role in other cancers remains unexplored.

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