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

Area of Science:

• Cell Biology
• Molecular Biology
• Oncology

Background:

• Zinc and ring finger 3 (ZNRF3) is a ubiquitin ligase crucial for Wnt receptor degradation.
• Protein tyrosine phosphatase receptor-type kappa (PTPRK) dephosphorylates ZNRF3, promoting its internalization.
• The protein tyrosine kinase (PTK) responsible for ZNRF3 phosphorylation remained unidentified.

Purpose of the Study:

• Identify the PTK that phosphorylates ZNRF3's 4Y motif.
• Investigate the role of MET signaling in ZNRF3 regulation.
• Elucidate the interplay between MET, ZNRF3, and Wnt signaling.

Main Methods:

• Co-immunoprecipitation assays to detect MET-ZNRF3 binding.
• Western blotting to assess 4Y motif phosphorylation.
• Gene depletion and pharmacological inhibition of MET.
• Analysis of Wnt receptor degradation and Wnt/β-catenin signaling.

Main Results:

• The proto-oncogene MET was identified as the kinase phosphorylating ZNRF3's 4Y motif.
• Hepatocyte growth factor (HGF) stimulation enhances MET-ZNRF3 interaction and 4Y phosphorylation.
• HGF-MET signaling inhibits ZNRF3-mediated Wnt receptor degradation, boosting Wnt/β-catenin signaling.
• MET inhibition or depletion increases ZNRF3 internalization and Wnt receptor degradation.

Conclusions:

• HGF-MET signaling phosphorylates ZNRF3, while PTPRK dephosphorylates it, creating a rheostat for Wnt signaling.
• MET acts as a critical regulator of ZNRF3 internalization and Wnt pathway activity.
• Targeting the MET-ZNRF3 axis presents a potential therapeutic strategy for Wnt-dependent diseases.