The adenomatous polyposis coli (APC) protein has a tumor-suppressor function by acting as a negative regulator of the Wnt signaling pathway. While its role as a tumor suppressor is well-defined, the post-translational modifications that regulate APC stability are not fully understood. Here we showed that MKRN1, an E3 ligase, could directly interact with and ubiquitylate APC, promoting its proteasomal degradation. In contrast, an E3 ligase-defective MKRN1 mutant was no longer capable of regulating APC, indicating that its E3 ligase activity is required for APC regulation by MKRN1. Strengthening these results, MKRN1 ablation resulted in reduced β-catenin activity and decreased expression of Wnt target genes. The ability of the Wnt-dependent pathway to induce cancer cell proliferation, migration, and invasion was impaired by MKRN1 depletion, but restored by simultaneous APC knockdown. Taken together, these results demonstrate that MKRN1 functions as a novel E3 ligase of APC that positively regulates Wnt/β-catenin-mediated biological processes.

中文翻译：

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MKRN1使腺瘤性息肉病的泛素化和降解增强了Wnt /β-catenin信号传导。

腺瘤性息肉病大肠杆菌（APC）蛋白通过充当Wnt信号通路的负调节剂而具有肿瘤抑制功能。尽管其作为肿瘤抑制剂的作用已明确定义，但调节APC稳定性的翻译后修饰尚不完全清楚。在这里，我们显示了MKRN1（一种E3连接酶）可以直接与APC相互作用并使其泛素化，从而促进其蛋白酶体降解。相反，E3连接酶缺陷的MKRN1突变体不再能够调节APC，表明其E3连接酶活性是MKRN1调节APC所必需的。加强这些结果，MKRN1切除导致β-catenin活性降低，Wnt目标基因表达降低。MKRN1耗竭削弱了Wnt依赖性途径诱导癌细胞增殖，迁移和侵袭的能力，但通过同时进行APC击倒来恢复。综上所述，这些结果表明，MKRN1充当APC的新型E3连接酶，可正向调节Wnt /β-catenin介导的生物过程。