Wnt/β‐catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt‐hypersensitive tumors that are susceptible to anti‐Wnt‐based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce β‐catenin‐mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with a ubiquitin‐independent suppressor role of the RNF43 cytosolic tail that involves Casein kinase 1 (CK1) binding and phosphorylation. Mechanistically, truncated RNF43 variants trap CK1 at the plasma membrane, thereby preventing β‐catenin turnover and propelling ligand‐independent target gene transcription. Gene editing of human colon stem cells shows that RNF43 truncations cooperate with p53 loss to drive a niche‐independent program for self‐renewal and proliferation. Moreover, these RNF43 variants confer decreased sensitivity to anti‐Wnt‐based therapy. Our data demonstrate the relevance of studying patient‐derived mutations for understanding disease mechanisms and improved applications of precision medicine.

中文翻译：

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RNF43截断陷阱CK1来驱动癌症中的非利基独立自我更新。

Wnt /β-catenin信号传导是组织更新过程中维持干细胞的主要途径，也是癌症突变的常见靶标。由于泛素连接酶RNF43的丧失而导致Wnt受体内吞功能受损，从而导致Wnt超敏性肿瘤易受基于Wnt的抗治疗作用。与该范式相反，我们鉴定出一类RNF43截断可诱使β-catenin介导的转录的癌症突变，尽管表现出保留的Wnt受体下调。这些突变干扰了涉及酪蛋白激酶1（CK1）结合和磷酸化的RNF43胞质尾巴的泛素依赖性抑制剂作用。从机制上讲，截短的RNF43变体将CK1捕获在质膜上，从而防止了β-catenin转换并推动了不依赖配体的靶基因的转录。对人类结肠干细胞的基因编辑显示，RNF43的截短与p53的缺失共同驱动了独立于利基的程序来进行自我更新和增殖。此外，这些RNF43变体降低了对基于抗Wnt疗法的敏感性。我们的数据表明，研究患者衍生的突变对于理解疾病机理和改善精密医学的应用具有重要意义。