WNK kinases control RNF43 plasma membrane levels to fine-tune WNT signaling
The E3 ubiquitin ligases RNF43 and ZNRF3 are key negative regulators of canonical WNT signaling, promoting turnover of the WNT receptors FRIZZLED and LRP5/6 at the plasma membrane. While their mechanism of action is well established, how RNF43/ZNRF3 themselves are regulated remains unclear. Here, we identify WNK kinases as novel upstream regulators of RNF43 through proximity labeling proteomics. Using gain- and loss-of-function approaches, we show that WNKs control RNF43 surface localization and thereby its ability to ubiquitinate and downregulate WNT receptors. Pharmacological inhibition of WNKs increases RNF43 membrane abundance and enhances WNT suppression - an effect abolished in RNF43/ZNRF3 double knockout cells and organoids. Mechanistically, WNK inhibition alters RNF43 trafficking and ubiquitination, revealing a role for WNKs in regulating its plasma membrane distribution. These findings define a new regulatory axis linking the pro-WNT activity of WNKs to RNF43/ZNRF3-mediated feedback inhibition. Targeting WNK now offers a novel therapeutic strategy to restore WNT pathway control in cancers with RSPO fusions or RNF43 mutations.
Authors
- Bon‐Kyoung Koo (ORCID: https://orcid.org/0000-0002-4134-8033)
- Gabriele Colozza (ORCID: https://orcid.org/0000-0003-4517-3389)
- Andrea Català-Bordes (ORCID: https://orcid.org/0000-0002-9634-9519)
- Sam B. Wu (ORCID: https://orcid.org/0000-0003-2594-7383)
- Katherina Tavernini (ORCID: https://orcid.org/0000-0003-3987-2167)
- Dong Woo Seo (ORCID: https://orcid.org/0009-0006-2208-7399)
- Madelon M. Maurice (ORCID: https://orcid.org/0000-0001-6885-5361)
- Ingrid Jordens (ORCID: https://orcid.org/0000-0001-7865-2816)
- Noelia Urbán (ORCID: https://orcid.org/0000-0003-4813-9274)
- Jeongmin Ha (ORCID: https://orcid.org/0000-0001-7232-4192)
- Eric Sosa (ORCID: https://orcid.org/0000-0001-5965-3477)
- Fiona Farnhammer (ORCID: https://orcid.org/0000-0003-4149-8215)
- Jihoon Kim (ORCID: https://orcid.org/0000-0002-3258-6953)
- SeungWoo Lee (ORCID: https://orcid.org/0000-0001-7919-1126)
Institutions
- University of Pisa (IT)
- Pohang University of Science and Technology (KR)
- Institute of Molecular Biotechnology (AT)
- University of Vienna (AT)
- Albert Einstein College of Medicine (US)
- Austrian Academy of Sciences (AT)
- Korea Advanced Institute of Science and Technology (KR)
- University of Zurich (CH)
- University Medical Center Utrecht (NL)
- ETH Zurich (CH)
- Institute for Basic Science (KR)
- Oncode Institute (NL)
- University Children's Hospital Zurich (CH)
- Vienna Biocenter (AT)
- Medical University of Vienna (AT)
- Sungkyunkwan University (KR)
Publication Details
- Journal
- Experimental & Molecular Medicine
- Published
- 2026-11-04
- DOI
- https://doi.org/10.1038/s12276-026-01871-4
- Citations
- 2
- Primary Topic
- Wnt/β-catenin signaling in development and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.70
Funders
- Austrian Science Fund
- National Institute of Mental Health
- National Institute of General Medical Sciences