The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer
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 emb...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/51248 |
| _version_ | 1811235983532752896 |
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| author | Ling-Shih Chang Minseong Kim Andrey Glinka Carmen Reinhard Christof Niehrs |
| author_facet | Ling-Shih Chang Minseong Kim Andrey Glinka Carmen Reinhard Christof Niehrs |
| author_sort | Ling-Shih Chang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:01:28Z |
| format | Article |
| id | doaj.art-893298afe7204b6cb05baedb04797b55 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:01:28Z |
| publishDate | 2020-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-893298afe7204b6cb05baedb04797b552022-12-22T03:33:50ZengeLife Sciences Publications LtdeLife2050-084X2020-01-01910.7554/eLife.51248The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizerLing-Shih Chang0https://orcid.org/0000-0003-0025-0862Minseong Kim1https://orcid.org/0000-0002-3927-4899Andrey Glinka2Carmen Reinhard3Christof Niehrs4https://orcid.org/0000-0002-9561-9302Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, GermanyDivision of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, GermanyDivision of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, GermanyDivision of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, GermanyDivision of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany; Institute of Molecular Biology (IMB), Mainz, GermanyA 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.https://elifesciences.org/articles/51248LRP6PTPRKspemann organizertyrosine phosphataseWntZNRF3 |
| spellingShingle | Ling-Shih Chang Minseong Kim Andrey Glinka Carmen Reinhard Christof Niehrs The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer eLife LRP6 PTPRK spemann organizer tyrosine phosphatase Wnt ZNRF3 |
| title | The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer |
| title_full | The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer |
| title_fullStr | The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer |
| title_full_unstemmed | The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer |
| title_short | The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer |
| title_sort | tumor suppressor ptprk promotes znrf3 internalization and is required for wnt inhibition in the spemann organizer |
| topic | LRP6 PTPRK spemann organizer tyrosine phosphatase Wnt ZNRF3 |
| url | https://elifesciences.org/articles/51248 |
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