IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
EMBO J. 2013 Jul 31;32(15):2140-57. doi: 10.1038/emboj.2013.149. Epub 2013 Jun 25.
How the cell converts graded signals into threshold-activated responses is a question of great biological relevance. Here, we uncover a nonlinear modality of epidermal growth factor receptor (EGFR)-activated signal transduction, by demonstrating that the ubiquitination of the EGFR at the PM is threshold controlled. The ubiquitination threshold is mechanistically determined by the cooperative recruitment of the E3 ligase Cbl, in complex with Grb2, to the EGFR. This, in turn, is dependent on the simultaneous presence of two phosphotyrosines, pY1045 and either one of pY1068 or pY1086, on the same EGFR moiety. The dose-response curve of EGFR ubiquitination correlate precisely with the non-clathrin endocytosis (NCE) mode of EGFR internalization. Finally, EGFR-NCE mechanistically depends on EGFR ubiquitination, as the two events can be simultaneously re-engineered on a phosphorylation/ubiquitination-incompetent EGFR backbone. Since NCE controls the degradation of the EGFR, our findings have implications for how the cell responds to increasing levels of EGFR signalling, by varying the balance of receptor signalling and degradation/attenuation.
细胞如何将分级信号转化为门控激活反应，这是一个具有重要生物学意义的问题。在这里，我们揭示了表皮生长因子受体（EGFR）激活信号转导的一种非线性模式，证明了 PM 处 EGFR 的泛素化受到门控控制。这种门控阈值的机制是由 Cbl E3 连接酶与 Grb2 复合物与 EGFR 的协同募集决定的。反过来，这又依赖于同一 EGFR 部分上的两个磷酸酪氨酸 pY1045 和 pY1068 或 pY1086 之一的同时存在。EGFR 泛素化的剂量反应曲线与 EGFR 内化的非网格蛋白内吞（NCE）模式精确相关。最后，EGFR-NCE 在机制上依赖于 EGFR 泛素化，因为这两个事件可以同时在磷酸化/泛素化失活的 EGFR 骨架上进行重新设计。由于 NCE 控制着 EGFR 的降解，我们的发现对于细胞如何通过改变受体信号转导和降解/衰减的平衡来响应 EGFR 信号的增加水平具有重要意义。
