The ability of cells to adapt their response to growth factors in relation to their environment is an essential aspect of tissue development and homeostasis. We found that signaling mediated by the Eph family of receptor tyrosine kinases from cell-cell contacts changed the cellular response to the growth factor EGF by modulating the vesicular trafficking of its receptor, EGFR. Eph receptor activation trapped EGFR in Rab5-positive early endosomes by inhibiting Akt-dependent vesicular recycling. By altering the spatial distribution of EGFR activity, EGF-promoted Akt signaling from the plasma membrane was suppressed, thereby inhibiting cell migration. In contrast, ERK signaling from endosomal EGFR was preserved to maintain a proliferative response to EGF stimulation. We also found that soluble extracellular signals engaging the G protein–coupled receptor Kiss1 (Kiss1R) similarly suppressed EGFR vesicular recycling to inhibit EGF-promoted migration. Eph or Kiss1R activation also suppressed EGF-promoted migration in Pten^−/− mouse embryonic fibroblasts, which exhibit increased constitutive Akt activity, and in MDA-MB-231 triple-negative breast cancer cells, which overexpress EGFR. The cellular environment can thus generate context-dependent responses to EGF stimulation by modulating EGFR vesicular trafficking dynamics.

细胞适应与其环境相关的生长因子反应的能力是组织发育和体内平衡的重要方面。我们发现由细胞接触引起的受体酪氨酸激酶的Eph家族介导的信号转导通过调节其受体EGFR的囊泡运输，改变了细胞对生长因子EGF的反应。Eph受体激活通过抑制Akt依赖的囊泡回收，将EGFR捕获在Rab5阳性的早期内体中。通过改变EGFR活性的空间分布，可以抑制EGF促进的质膜Akt信号传导，从而抑制细胞迁移。相反，保留了来自内体EGFR的ERK信号传导，以维持对EGF刺激的增殖反应。我们还发现，参与G蛋白偶联受体Kiss1（Kiss1R）的可溶性细胞外信号同样抑制EGFR囊泡循环，从而抑制EGF促进的迁移。Eph或Kiss1R激活还抑制了EGF促进的迁移Pten ^-/-小鼠胚胎成纤维细胞，表现出增强的Akt组成活性，在MDA-MB-231三阴性乳腺癌细胞中，EGFR过表达。因此，细胞环境可以通过调节EGFR囊泡运输动力学来产生对EGF刺激的背景相关反应。