Brüggemann Yannick, Karajannis Lisa S, Stanoev Angel, Stallaert Wayne, Bastiaens Philippe I H
Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Str.11, 44227 Dortmund, Germany.
Faculty of Chemistry and Chemical Biology, TU Dortmund, Otto-Hahn-Str. 6, 44227 Dortmund, Germany.
Sci Signal. 2021 May 18;14(683):eabd9943. doi: 10.1126/scisignal.abd9943.
Growth factor-dependent vesicular dynamics allow cells to regulate the spatial distribution of growth factor receptors and thereby their coupling to downstream signaling effectors that guide cellular responses. We found that the ErbB ligands epidermal growth factor (EGF) and heregulin (HRG) generated distinct spatiotemporal patterns of cognate receptor activities to activate distinct subcellular pools of the extracellular signal-regulated kinase (Erk). Sustained plasma membrane activity of the receptor tyrosine kinases ErbB2/ErbB3 signaled to Erk complexed with the scaffold protein KSR to promote promigratory EphA2 phosphorylation and cellular motility upon HRG stimulation. In contrast, receptor-saturating EGF stimuli caused proliferation-inducing transient activation of cytoplasmic Erk due to the rapid internalization of EGF receptors (EGFR or ErbB1) toward endosomes. Paradoxically, promigratory signaling mediated by Erk complexed to KSR was sustained at low EGF concentrations by vesicular recycling that maintained steady-state amounts of active, phosphorylated EGFR at the plasma membrane. Thus, the effect of ligand identity and concentration on determining ErbB vesicular dynamics constitutes a mechanism by which cells can transduce growth factor composition through spatially distinct Erk pools to enable functionally diverse cellular responses.
生长因子依赖性囊泡动力学使细胞能够调节生长因子受体的空间分布，从而调节其与引导细胞反应的下游信号效应器的偶联。我们发现，表皮生长因子（EGF）和神经调节蛋白（HRG）这两种ErbB配体产生了不同的时空模式的同源受体活性，以激活细胞外信号调节激酶（Erk）的不同亚细胞池。受体酪氨酸激酶ErbB2/ErbB3持续的质膜活性向与支架蛋白KSR复合的Erk发出信号，以促进HRG刺激后促迁移的EphA2磷酸化和细胞运动。相反，受体饱和的EGF刺激导致细胞质Erk的增殖诱导性瞬时激活，这是由于EGF受体（EGFR或ErbB1）迅速内化至内体所致。矛盾的是，与KSR复合的Erk介导的促迁移信号在低EGF浓度下通过囊泡循环得以维持，囊泡循环维持了质膜上活性磷酸化EGFR的稳态量。因此，配体特性和浓度对确定ErbB囊泡动力学的影响构成了一种机制，通过该机制细胞可以通过空间上不同的Erk池转导生长因子组成，从而实现功能多样的细胞反应。
