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.

中文翻译：

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肿瘤抑制物PTPRK促进ZNRF3内在化，并且是Spemann组织者抑制Wnt所必需的

Spemann组织者功能的标志是其表达Wnt拮抗剂的表达，该拮抗剂调节轴向胚胎的形态。在这里，我们确定肿瘤抑制蛋白酪氨酸磷酸酶受体型κ（Ptprk），作为Spemann组织者的Wnt抑制剂。我们显示PTPRK通过跨膜E3泛素连接酶ZNRF3起作用，Wnt信号的负调节剂促进Wnt受体降解，这也在组织者中表达。ptprk的缺乏会增加Wnt信号传导，导致Spemann组织效应基因的表达减少，并诱导头部和轴向缺陷。我们在ZNRF3中确定一个'4Y'内吞信号，Ptprk保持未磷酸化以促进Wnt受体耗竭。