WNK kinases control RNF43 plasma membrane levels to fine-tune WNT signaling
Year: 2026
Type: article
Abstract: 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.
Institutions: University of Pisa, Institute of Molecular Biotechnology, Austrian Academy of Sciences, Vienna Biocenter, University Medical Center Utrecht, Oncode Institute, Albert Einstein College of Medicine, Institute for Basic Science, ETH Zurich, University of Vienna, Medical University of Vienna, University of Zurich, University Children's Hospital Zurich, Pohang University of Science and Technology, Korea Advanced Institute of Science and Technology, Sungkyunkwan University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,490
OpenAlex ID: W4414945788