Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
Cancer Res. 2021 Sep 1;81(17):4441-4454. doi: 10.1158/0008-5472.CAN-21-1112. Epub 2021 Jun 7.
Leucine-rich repeat-containing G protein-coupled receptors 4, 5, and 6 (LGR4/5/6) play critical roles in development and cancer. The widely accepted mechanism is that these proteins, together with their R-spondin ligands, stabilize Wnt receptors, thus potentiating Wnt signaling. Here we show that LGR4 enhanced breast cancer cell metastasis even when Wnt signaling was deactivated pharmacologically or genetically. Furthermore, LGR4 mutants that cannot potentiate Wnt signaling nevertheless promoted breast cancer cell migration and invasion and breast cancer metastasis . Multiomic screening identified EGFR as a crucial mediator of LGR4 activity in cancer progression. Mechanistically, LGR4 interacted with EGFR and blocked EGFR ubiquitination and degradation, resulting in persistent EGFR activation. Together, these data uncover a Wnt-independent LGR4-EGFR signaling axis with broad implications for cancer progression and targeted therapy. SIGNIFICANCE: This work demonstrates a Wnt-independent mechanism by which LGR4 promotes cancer metastasis..
富含亮氨酸重复的 G 蛋白偶联受体 4、5 和 6（LGR4/5/6）在发育和癌症中发挥关键作用。被广泛接受的机制是，这些蛋白与它们的 R - 分泌蛋白配体一起稳定 Wnt 受体，从而增强 Wnt 信号。在这里，我们表明 LGR4 增强了乳腺癌细胞转移，即使 Wnt 信号在药理学或遗传学上被失活。此外，不能增强 Wnt 信号的 LGR4 突变体仍然促进了乳腺癌细胞的迁移和侵袭以及乳腺癌转移。多组学筛选鉴定出 EGFR 是 LGR4 在癌症进展中活性的关键介质。在机制上，LGR4 与 EGFR 相互作用并阻止 EGFR 的泛素化和降解，导致 EGFR 的持续激活。总之，这些数据揭示了一个独立于 Wnt 的 LGR4-EGFR 信号轴，对癌症进展和靶向治疗具有广泛的意义。意义：这项工作证明了 LGR4 促进癌症转移的一种独立于 Wnt 的机制。
