Department of Biological Sciences, University of Toledo, Toledo, OH 43606, USA.
J Cell Sci. 2024 Oct 1;137(19). doi: 10.1242/jcs.262181. Epub 2024 Oct 14.
SGEF (also known as ARHGEF26), a RhoG specific GEF, can form a ternary complex with the Scribble polarity complex proteins Scribble and Dlg1, which regulates the formation and maintenance of adherens junctions and barrier function of epithelial cells. Notably, silencing SGEF results in a dramatic downregulation of both E-cadherin and ZO-1 (also known as TJP1) protein levels. However, the molecular mechanisms involved in the regulation of this pathway are not known. Here, we describe a novel signaling pathway governed by the Scribble-SGEF-Dlg1 complex. Our results show that the three members of the ternary complex are required to maintain the stability of the apical junctions, ZO-1 protein levels and tight junction (TJ) permeability. In contrast, only SGEF is necessary to regulate E-cadherin levels. The absence of SGEF destabilizes the E-cadherin-catenin complex at the membrane, triggering a positive feedback loop that exacerbates the phenotype through the repression of E-cadherin transcription in a process that involves the internalization of E-cadherin by endocytosis, β-catenin signaling and the transcriptional repressor Slug (also known as SNAI2).
SGEF（也称为 ARHGEF26）是一种 RhoG 特异性鸟苷酸交换因子，能够与 Scribble 极性复合物蛋白 Scribble 和Dlg1 形成三元复合物，调节上皮细胞黏附连接的形成和维持以及屏障功能。值得注意的是，沉默 SGEF 会导致 E-钙黏蛋白和 ZO-1（也称为 TJP1）蛋白水平显著下调。然而，调控该通路的分子机制尚不清楚。在这里，我们描述了一个由 Scribble-SGEF-Dlg1 复合物调控的新型信号通路。我们的结果表明，三元复合物的三个成员对于维持顶端连接、ZO-1 蛋白水平和紧密连接（TJ）通透性的稳定性是必需的。相比之下，只有 SGEF 能够调节 E-钙黏蛋白水平。SGEF 的缺失会使膜上的 E-钙黏蛋白-连环蛋白复合物不稳定，触发正反馈回路，通过内吞作用使 E-钙黏蛋白内化、β-连环蛋白信号和转录抑制因子 Slug（也称为 SNAI2）来加剧表型，从而抑制 E-钙黏蛋白转录。
