Research Center for Dynamic Living Systems, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
J Cell Sci. 2023 Aug 15;136(16). doi: 10.1242/jcs.261199. Epub 2023 Aug 21.
The ErbB-family receptors play pivotal roles in the proliferation, migration and survival of epithelial cells. Because our knowledge on the ErbB-family receptors has been largely obtained by the exogenous application of their ligands, it remains unknown to what extent each of the ErbB members contributes to these outputs. We here knocked out each ErbB gene, various combinations of ErbB genes or all ErbB genes in Madin-Darby canine kidney cells to delineate the contribution of each gene. ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) activation waves during collective cell migration were mediated primarily by ErbB1 and secondarily by the ErbB2 and ErbB3 heterodimer. Either ErbB1 or the ErbB2 and ErbB3 complex was sufficient for the G1/S progression. The saturation cell density was markedly reduced in cells deficient in all ErbB proteins, but not in cells retaining only ErbB2, which cannot bind to ligands. Thus, a ligand-independent ErbB2 activity is sufficient for preventing apoptosis at high cell density. In short, systematic knockout of ErbB-family genes has delineated the roles of each ErbB receptor.
表皮细胞的增殖、迁移和存活过程中，ErbB 家族受体发挥着关键作用。由于我们对 ErbB 家族受体的认识主要是通过其配体的外源性应用获得的，因此，每个 ErbB 成员在多大程度上促进这些作用仍然未知。我们在此敲除了 Madin-Darby 犬肾细胞中的每个 ErbB 基因、各种 ErbB 基因组合或所有 ErbB 基因，以描绘每个基因的贡献。在细胞集体迁移过程中，ERK1 和 ERK2（ERK1/2，也分别称为 MAPK3 和 MAPK1）激活波主要由 ErbB1 介导，其次由 ErbB2 和 ErbB3 异二聚体介导。ErbB1 或 ErbB2 和 ErbB3 复合物足以促进 G1/S 期进展。在缺乏所有 ErbB 蛋白的细胞中，饱和细胞密度明显降低，但在仅保留不能结合配体的 ErbB2 的细胞中则没有降低。因此，一种无需配体的 ErbB2 活性足以防止在高细胞密度下发生细胞凋亡。总之，ErbB 家族基因的系统敲除描绘了每个 ErbB 受体的作用。
