Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors
Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors
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DOI：
10.1038/nature11308
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发表时间：
2012-08-30
期刊：
影响因子：
64.8
通讯作者：
Clevers, Hans
中科院分区：
文献类型：
--
作者：
Koo, Bon-Kyoung;Spit, Maureen;Clevers, Hans
LGR 5（+）干细胞位于隐窝底部，与提供Wnt、Notch和表皮生长因子信号的潘氏细胞混合（1）。在这里，我们发现相关的RNF43和ZNRF3跨膜E3泛素连接酶在LGR 5（+）干细胞中唯一表达。在小鼠肠上皮中同时缺失编码这些蛋白质的两个基因会诱导含有大量潘氏和LGR 5（+）干细胞的快速生长的腺瘤。在体外，当Wnt分泌被抑制时，来源于这些腺瘤的类器官的生长被阻止，表明腺瘤干细胞依赖于腺瘤潘氏细胞产生的Wnt。在HEK293T人癌细胞系中，RNF43的表达阻断Wnt应答并将表面表达的卷曲受体靶向溶酶体。在RNF43突变的结肠直肠癌细胞系HCT 116中，RNF43表达的重建消除了其对外源性Wnt的反应。我们得出结论，RNF43和ZNRF3通过选择性泛素化卷曲受体来减少Wnt信号，从而靶向这些Wnt受体进行降解。
LGR5(+) stem cells reside at crypt bottoms, intermingled with Paneth cells that provide Wnt, Notch and epidermal growth factor signals(1). Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin ligases are uniquely expressed in LGR5(+) stem cells. Simultaneous deletion of the two genes encoding these proteins in the intestinal epithelium of mice induces rapidly growing adenomas containing high numbers of Paneth and LGR5(+) stem cells. In vitro, growth of organoids derived from these adenomas is arrested when Wnt secretion is inhibited, indicating a dependence of the adenoma stem cells on Wnt produced by adenoma Paneth cells. In the HEK293T human cancer cell line, expression of RNF43 blocks Wnt responses and targets surface-expressed frizzled receptors to lysosomes. In the RNF43-mutant colorectal cancer cell line HCT116, reconstitution of RNF43 expression removes its response to exogenous Wnt. We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation.