Frey Mark R, Golovin Anastasia, Polk D Brent
Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2576, USA.
J Biol Chem. 2004 Oct 22;279(43):44513-21. doi: 10.1074/jbc.M406253200. Epub 2004 Aug 16.
Members of the epidermal growth factor (EGF) family of ligands and their receptors regulate migration and growth of intestinal epithelial cells. However, our understanding of the signal transduction pathways determining these responses is incomplete. In this study we tested the hypothesis that p38 is required for EGF-stimulated intestinal epithelial monolayer restitution. EGF-stimulated migration in a wound closure model required continuous presence of ligand for several hours for maximal response, suggesting a requirement for sustained signal transduction pathway activation. In this regard, prolonged exposure of cells to EGF activated p38 for up to 5 h. Furthermore genetic or pharmacological blockade of p38 signaling inhibited the ability of EGF to accelerate wound closure. Interestingly p38 inhibition was associated with increased EGF-stimulated ERK1/ERK2 phosphorylation and cell proliferation, suggesting that p38 regulates the balance of proliferation/migration signaling in response to EGF receptor activity. Activation of p38 in intestinal epithelial cells through EGF receptor was abolished by blockade of Src family tyrosine kinase signaling but not inhibition of phosphatidylinositol 3-kinase or protein kinase C. Taken together, these data suggest that Src family kinase-dependent p38 activation is a key component of a signaling switch routing EGF-stimulated responses to epithelial cell migration/restitution rather than proliferation during wound closure.
表皮生长因子（EGF）家族配体及其受体的成员调节肠道上皮细胞的迁移和生长。然而，我们对决定这些反应的信号转导途径的理解并不完整。在本研究中，我们测试了一个假说，即p38是EGF刺激的肠道上皮单层修复所必需的。在伤口闭合模型中，EGF刺激的迁移需要配体持续存在数小时才能产生最大反应，这表明需要持续激活信号转导途径。在这方面，细胞长时间暴露于EGF可使p38激活长达5小时。此外，对p38信号的基因或药理学阻断抑制了EGF加速伤口闭合的能力。有趣的是，p38抑制与EGF刺激的ERK1/ERK2磷酸化增加和细胞增殖有关，这表明p38调节对EGF受体活性的增殖/迁移信号平衡。通过阻断Src家族酪氨酸激酶信号，但不抑制磷脂酰肌醇3激酶或蛋白激酶C，可消除EGF受体对肠道上皮细胞中p38的激活。综上所述，这些数据表明，Src家族激酶依赖性p38激活是信号转导开关的关键组成部分，该开关在伤口闭合期间将EGF刺激的反应导向上皮细胞迁移/修复而非增殖。
