WNK kinase regulates plasma membrane levels of the WNT inhibitor RNF43
Colozza, G.; Jordens, I.; Sosa, E. A.; Ha, j.; Wu, S.; Tavernini, K.; Catala, A.; Farnhammer, F.; Urban Avellaneda, N.; Maurice, M.; Koo, B.-K.
Show 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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Protein proximity networks and functional evaluation of the Casein Kinase 1 γ family reveals unique roles for CK1γ3 in WNT signaling 97%
- Mapping the MOB proteins' proximity network reveals a unique interaction between human MOB3C and the RNase P complex 96%
- The X-linked intellectual disability gene product and E3 ubiquitin ligase KLHL15 degrades doublecortin proteins to constrain neuronal dendritogenesis 96%
Similar papers in this journal
- A complex of distal appendage-associated kinases linked to human disease regulates ciliary trafficking and stability 96%
- Lysosomes are Required for Early Dorsal Signaling in the Xenopus Embryo 96%
- Unprecedentedly efficient CUG initiation of an overlapping reading frame in POLG mRNA yields novel protein POLGARF 96%
Similar papers in this journal
- HIRA loss transforms FH-deficient cells 96%
- C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility 96%
- Ras-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.