The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer
The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer
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DOI：
10.7554/elife.51248
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发表时间：
2020-01-14
期刊：
影响因子：
7.7
通讯作者：
Niehrs, Christof
中科院分区：
文献类型：
--
作者：
Chang, Ling-Shih;Kim, Minseong;Niehrs, Christof
Spemann组织者功能的一个标志是其调节轴向胚胎模式的Wnt拮抗剂的表达。在这里，我们确定了肿瘤抑制蛋白酪氨酸磷酸酶受体型κ（PTH 4），作为Wnt抑制剂在人类癌细胞和非洲爪蟾胚胎的Spemann组织者。我们表明，通过跨膜E3泛素连接酶ZNRF 3，Wnt信号的负调节促进Wnt受体降解，这也是在组织者中表达的PTR 4的行为。非洲爪蟾Ptprk缺陷增加Wnt信号传导，导致Spemann组织者效应基因表达减少，并诱导头部和轴向缺陷。我们确定了ZNRF 3中的“4 Y”内吞信号，PTNRF 3保持未磷酸化以促进Wnt受体耗尽。我们发现PTPRK是Wnt受体转换的负调节因子，这为其肿瘤抑制功能提供了理论基础，并揭示了在PTPRK-RSPO 3复发性癌症融合中，两种融合伴侣实际上都编码ZNRF 3调节因子。
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.