Department I, Institute of Anatomy and Cell Biology, Ludwig Maximilians University Munich, Pettenkoferstr. 11, 80336, Munich, Germany.
Department of General, Visceral, Vascular and Paediatric Surgery, Julius-Maximilians-Universität, Oberdürrbacher Str. 6, 97080, Würzburg, Germany.
Cell Mol Life Sci. 2018 Nov;75(22):4251-4268. doi: 10.1007/s00018-018-2869-x. Epub 2018 Jul 6.
Rapidly renewing epithelial tissues such as the intestinal epithelium require precise tuning of intercellular adhesion and proliferation to preserve barrier integrity. Here, we provide evidence that desmoglein 2 (Dsg2), an adhesion molecule of desmosomes, controls cell adhesion and proliferation via epidermal growth factor receptor (EGFR) signaling. Dsg2 is required for EGFR localization at intercellular junctions as well as for Src-mediated EGFR activation. Src binds to EGFR and is required for localization of EGFR and Dsg2 to cell-cell contacts. EGFR is critical for cell adhesion and barrier recovery. In line with this, Dsg2-deficient enterocytes display impaired barrier properties and increased cell proliferation. Mechanistically, Dsg2 directly interacts with EGFR and undergoes heterotypic-binding events on the surface of living enterocytes via its extracellular domain as revealed by atomic force microscopy. Thus, our study reveals a new mechanism by which Dsg2 via Src shapes EGFR function towards cell adhesion.
快速更新的上皮组织，如肠道上皮，需要精确调节细胞间的黏附和增殖，以维持屏障的完整性。在这里，我们提供的证据表明桥粒黏附分子 2（Dsg2）通过表皮生长因子受体（EGFR）信号通路控制细胞黏附和增殖。Dsg2 对于 EGFR 在细胞间连接的定位以及Src 介导的 EGFR 激活是必需的。Src 与 EGFR 结合，对于 EGFR 和 Dsg2 到细胞-细胞接触的定位是必需的。EGFR 对于细胞黏附和屏障恢复是至关重要的。与此一致的是，Dsg2 缺陷的肠细胞显示出受损的屏障特性和增加的细胞增殖。从机制上讲，Dsg2 通过 Src 直接与 EGFR 相互作用，并通过原子力显微镜揭示的其细胞外结构域在活肠细胞表面上发生异型结合事件。因此，我们的研究揭示了 Dsg2 通过 Src 形成 EGFR 功能以实现细胞黏附的新机制。
