The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer

Elife. 2020 Jan 14:9:e51248. doi: 10.7554/eLife.51248.

Abstract

A hallmark of Spemann organizer function is its expression of Wnt antagonists that regulate axial embryonic patterning. Here we identify the tumor suppressor Protein tyrosine phosphatase receptor-type kappa (PTPRK), as a Wnt inhibitor in human cancer cells and in the Spemann organizer of Xenopus embryos. We show that PTPRK acts via the transmembrane E3 ubiquitin ligase ZNRF3, a negative regulator of Wnt signaling promoting Wnt receptor degradation, which is also expressed in the organizer. Deficiency of Xenopus Ptprk increases Wnt signaling, leading to reduced expression of Spemann organizer effector genes and inducing head and axial defects. We identify a '4Y' endocytic signal in ZNRF3, which PTPRK maintains unphosphorylated to promote Wnt receptor depletion. Our discovery of PTPRK as a negative regulator of Wnt receptor turnover provides a rationale for its tumor suppressive function and reveals that in PTPRK-RSPO3 recurrent cancer fusions both fusion partners, in fact, encode ZNRF3 regulators.

Keywords: LRP6; PTPRK; Wnt; ZNRF3; cell biology; developmental biology; human; spemann organizer; tyrosine phosphatase; xenopus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning / genetics
  • Endocytosis
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
  • Organizers, Embryonic / metabolism
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism*
  • Signal Transduction
  • Ubiquitin-Protein Ligases / metabolism*
  • Wnt Proteins / antagonists & inhibitors*
  • Xenopus Proteins / metabolism
  • Xenopus laevis
  • beta Catenin / metabolism

Substances

  • LRP6 protein, Xenopus
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Wnt Proteins
  • Xenopus Proteins
  • beta Catenin
  • Ubiquitin-Protein Ligases
  • ZNRF3 protein, human
  • PTPRK protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2

Associated data

  • GEO/GSE75278