Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Str.11, 44227 Dortmund, Germany.
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264, USA.
Sci Signal. 2018 Jul 31;11(541):eaat0114. doi: 10.1126/scisignal.aat0114.
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 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.
细胞根据其所处的环境，改变对生长因子反应的能力是组织发育和稳态的一个重要方面。我们发现细胞-细胞接触处的 Eph 家族受体酪氨酸激酶所介导的信号转导，通过调节表皮生长因子受体（EGFR）的囊泡运输，改变了细胞对生长因子 EGF 的反应。Eph 受体的激活通过抑制 Akt 依赖性囊泡再循环，将 EGFR 困在 Rab5 阳性早期内体中。通过改变 EGFR 活性的空间分布，抑制了来自质膜的 EGF 促进的 Akt 信号转导，从而抑制细胞迁移。相比之下，来自内体 EGFR 的 ERK 信号转导得以保留，以维持对 EGF 刺激的增殖反应。我们还发现，与 G 蛋白偶联受体 Kiss1（Kiss1R）结合的可溶性细胞外信号同样抑制 EGFR 的囊泡再循环，从而抑制 EGF 促进的迁移。Eph 或 Kiss1R 的激活也抑制了具有较高组成性 Akt 活性的小鼠胚胎成纤维细胞以及过表达 EGFR 的 MDA-MB-231 三阴性乳腺癌细胞中 EGF 促进的迁移。因此，细胞环境可以通过调节 EGFR 囊泡运输动力学，对 EGF 刺激产生上下文相关的反应。
