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Elife January 14, 2020; 9

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

Chang LS , Kim M , Glinka A , Reinhard C , Niehrs C .

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.

PubMed ID: 31934854
PMC ID: PMC6996932
Article link: Elife
Grant support: [+]
Genes referenced: angptl4 bambi chrd.1 ctnnb1 dkk1 foxg1 frzb gsc lrp6 not otx2 ptprk sox3 znrf3
GO keywords: anterior/posterior axis specification [+]
Morpholinos: ctnnb1 MO1 lrp6 MO1 ptprk MO1 znrf3 MO1 znrf3 MO2

Phenotypes: Xtr WT + hsu. ZNRF3 (Fig. 5 supp1, C) [+]

Article Images: [+] show captions
References [+] :
Anders, Furin-, ADAM 10-, and gamma-secretase-mediated cleavage of a receptor tyrosine phosphatase and regulation of beta-catenin's transcriptional activity. 2006, Pubmed

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