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

  1. Ling-Shih Chang
  2. Minseong Kim
  3. Andrey Glinka
  4. Carmen Reinhard
  5. Christof Niehrs  Is a corresponding author
  1. Deutsches Krebsforschungszentrum (DKFZ), Germany

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 of the Spemann organizer. 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 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.

Data availability

All data generated or analysed during this study are included in the manuscript.

The following previously published data sets were used

Article and author information

Author details

  1. Ling-Shih Chang

    Division of Molecular Embryology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Minseong Kim

    Division of Molecular Embryology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Andrey Glinka

    Division of Molecular Embryology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Carmen Reinhard

    Division of Molecular Embryology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Christof Niehrs

    Division of Molecular Embryology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
    For correspondence
    niehrs@dkfz-heidelberg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9561-9302

Funding

Deutsche Forschungsgemeinschaft (CRC1324)

  • Ling-Shih Chang
  • Minseong Kim
  • Andrey Glinka
  • 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.

Ethics

Animal experimentation: All Xenopus experiments were approved by the state review board of Baden-Wuerttemberg , Germany (License number: G-13/186 & G-141/18) and performed according to the federal and institutional guideline.

Reviewing Editor

  1. Roel Nusse, Stanford University, United States

Version history

  1. Received: August 21, 2019
  2. Accepted: January 12, 2020
  3. Accepted Manuscript published: January 14, 2020 (version 1)
  4. Version of Record published: February 3, 2020 (version 2)

Copyright

© 2020, Chang et al.

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.

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  1. Ling-Shih Chang
  2. Minseong Kim
  3. Andrey Glinka
  4. Carmen Reinhard
  5. Christof Niehrs
(2020)
The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer
eLife 9:e51248.
https://doi.org/10.7554/eLife.51248

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