TY - JOUR TI - A MET-PTPRK kinase-phosphatase rheostat controls ZNRF3 and Wnt signaling AU - Kim, Minseong AU - Reinhard, Carmen AU - Niehrs, Christof A2 - Nusse, Roel A2 - Eisen, Michael B A2 - Nusse, Roel VL - 10 PY - 2021 DA - 2021/09/30 SP - e70885 C1 - eLife 2021;10:e70885 DO - 10.7554/eLife.70885 UR - https://doi.org/10.7554/eLife.70885 AB - Zinc and ring finger 3 (ZNRF3) is a transmembrane E3 ubiquitin ligase that targets Wnt receptors for ubiquitination and lysosomal degradation. Previously, we showed that dephosphorylation of an endocytic tyrosine motif (4Y motif) in ZNRF3 by protein tyrosine phosphatase receptor-type kappa (PTPRK) promotes ZNRF3 internalization and Wnt receptor degradation (Chang et al 2020). However, a responsible protein tyrosine kinase(s) (PTK) phosphorylating the 4Y motif remained elusive. Here we identify the proto-oncogene MET (mesenchymal-epithelial transition factor) as a 4Y kinase. MET binds to ZNRF3 and induces 4Y phosphorylation, stimulated by the MET ligand HGF (hepatocyte growth factor, scatter factor). HGF-MET signaling reduces ZNRF3-dependent Wnt receptor degradation thereby enhancing Wnt/β-catenin signaling. Conversely, depletion or pharmacological inhibition of MET promotes the internalization of ZNRF3 and Wnt receptor degradation. We conclude that HGF-MET signaling phosphorylates- and PTPRK dephosphorylates ZNRF3 to regulate ZNRF3 internalization, functioning as a rheostat for Wnt signaling that may offer novel opportunities for therapeutic intervention. KW - endocytosis KW - HGF-MET KW - PTPRK KW - tyrosine kinases KW - Wnt signaling KW - ZNRF3 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -