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

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Ling-Shih Chang1, Minseong Kim1, Andrey Glinka1

  • 1Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.

Elife
|January 15, 2020
PubMed

Insights

Protein tyrosine phosphatase receptor-type kappa (PTPRK) acts as a Wnt inhibitor in human cancers and embryonic development. It regulates Wnt signaling by controlling receptor degradation, impacting axial patterning and tumor suppression.

Area of Science:

  • Developmental Biology
  • Cancer Biology
  • Molecular Cell Biology

Background:

  • The Spemann organizer is crucial for embryonic axial patterning and expresses Wnt antagonists.
  • Wnt signaling pathways are vital in both embryonic development and cancer progression.

Purpose of the Study:

  • To identify novel Wnt antagonists involved in Spemann organizer function.
  • To elucidate the role of Protein tyrosine phosphatase receptor-type kappa (PTPRK) in Wnt signaling and embryonic patterning.
  • To understand the mechanism by which PTPRK regulates Wnt signaling and its implications in cancer.

Main Methods:

  • Expression analysis of PTPRK and ZNRF3 in Xenopus embryos and human cancer cells.
  • Functional studies involving knockdown or deficiency of PTPRK in Xenopus embryos.
  • Biochemical assays to investigate the interaction between PTPRK, ZNRF3, and Wnt receptors.
  • Analysis of PTPRK-RSPO3 cancer fusions.

Main Results:

  • PTPRK identified as a Wnt inhibitor in human cancer cells and the Xenopus Spemann organizer.
  • PTPRK regulates Wnt signaling by interacting with ZNRF3, promoting Wnt receptor degradation.
  • Loss of PTPRK in Xenopus embryos leads to increased Wnt signaling, affecting gene expression and causing developmental defects.
  • PTPRK maintains ZNRF3 in an unphosphorylated state, facilitating Wnt receptor depletion via a '4Y' endocytic signal.

Conclusions:

  • PTPRK is a key regulator of Wnt signaling through modulation of Wnt receptor turnover.
  • PTPRK's role as a negative regulator of Wnt signaling provides a mechanistic basis for its tumor suppressive function.
  • Recurrent PTPRK-RSPO3 cancer fusions involve regulators of ZNRF3, highlighting the importance of this pathway in cancer.
Keywords:
LRP6PTPRKWntZNRF3cell biologydevelopmental biologyhumanspemann organizertyrosine phosphatasexenopus

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