A MET-PTPRK kinase-phosphatase rheostat controls ZNRF3 and Wnt signalling

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Abstract

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 signalling reduces ZNRF3-dependent Wnt receptor degradation thereby enhancing Wnt/b-catenin signalling. Conversely, depletion or pharmacological inhibition of MET promotes internalization of ZNRF3 and Wnt receptor degradation. We conclude that HGF-MET signalling phosphorylates- and PTPRK dephosphorylates ZNRF3 to regulate ZNRF3 internalization, functioning as a rheostat for Wnt signalling that may offer novel opportunities for therapeutic intervention.

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All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for every figures.

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Minseong Kim

Division of Molecular Embryology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3927-4899
Carmen Reinhard

Division of Molecular Embryology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

Competing interests
The authors declare that no competing interests exist.
Christof Niehrs

Division of Molecular Embryology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

For correspondence
niehrs@dkfz.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9561-9302

Funding

Deutsche Forschungsgemeinschaft (SFB 1324)

Minseong Kim
Carmen Reinhard
Christof Niehrs

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.