Mammalian LGR5 and LGR4, markers of adult stem cells, are involved in many physiological functions by enhancing WNT signaling. However, whether LGR5 and LGR4 are coupled to other intracellular signaling pathways to regulate stem cell function remains unknown. Here, we show that LGR5 and LGR4 can constitutively activate NF‐κB signaling in a ligand‐independent manner, which is dependent on their C‐termini, but independent of receptor endocytosis. Moreover, the C‐termini of LGR5/4 interact with TROY, which is required for activating NF‐κB signaling. In small intestinal crypt organoids, overexpression of a C‐terminal deletion mutant of LGR5 inhibits the growth and bud formation of organoids, whereas overexpression of the R‐spondin‐binding mutant of LGR5 that is defective for WNT signaling can still promote organoid growth. Our study reveals that NF‐κB signaling, regulated by LGR5 and LGR4, plays an important role in the survival of colon cancer cells and the growth of intestinal crypts. Our findings also suggest that LGR5/4‐induced NF‐κB signaling and WNT signaling may co‐regulate the growth of LGR5+ adult stem cells and intestinal crypts.

中文翻译：

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LGR5组成性激活NF-κB信号以调节肠隐窝的生长

哺乳动物 LGR5 和 LGR4 是成体干细胞的标志物，通过增强 WNT 信号参与许多生理功能。然而，LGR5 和 LGR4 是否与其他细胞内信号通路偶联以调节干细胞功能仍然未知。在这里，我们表明 LGR5 和 LGR4 可以以不依赖配体的方式组成性激活 NF-κB 信号，这依赖于它们的 C 末端，但不依赖于受体内吞作用。此外，LGR5/4 的 C 末端与激活 NF-κB 信号所需的 TROY 相互作用。在小肠隐窝类器官中，LGR5 C 端缺失突变体的过度表达抑制类器官的生长和芽形成，而 WNT 信号传导缺陷的 LGR5 的 R-spondin 结合突变体的过度表达仍然可以促进类器官的生长。我们的研究表明，受 LGR5 和 LGR4 调节的 NF-κB 信号传导在结肠癌细胞的存活和肠隐窝的生长中起着重要作用。我们的研究结果还表明，LGR5/4 诱导的 NF-κB 信号和 WNT 信号可能共同调节 LGR5+ 成体干细胞和肠隐窝的生长。