Institute of Structural and Molecular Biology, University College London, London, UK.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2021 Apr 23;12(1):2424. doi: 10.1038/s41467-021-22603-4.
Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Fast Endophilin-mediated endocytosis, FEME, is not constitutively active but triggered upon receptor activation. High levels of growth factors induce spontaneous FEME, which can be suppressed upon serum starvation. This suggested a role for protein kinases in this growth factor receptor-mediated regulation. Using chemical and genetic inhibition, we find that Cdk5 and GSK3β are negative regulators of FEME. They antagonize the binding of Endophilin to Dynamin-1 and to CRMP4, a Plexin A1 adaptor. This control is required for proper axon elongation, branching and growth cone formation in hippocampal neurons. The kinases also block the recruitment of Dynein onto FEME carriers by Bin1. As GSK3β binds to Endophilin, it imposes a local regulation of FEME. Thus, Cdk5 and GSK3β are key regulators of FEME, licensing cells for rapid uptake by the pathway only when their activity is low.
内吞作用介导了细胞对微量营养素和细胞表面蛋白的摄取。快速内吞作用（Fast Endophilin-mediated endocytosis，FEME）不是组成性激活的，而是在受体激活时触发的。高水平的生长因子诱导自发的 FEME，而血清饥饿可以抑制其发生。这表明蛋白激酶在这种生长因子受体介导的调节中发挥作用。通过化学和遗传抑制，我们发现 Cdk5 和 GSK3β 是 FEME 的负调控因子。它们拮抗内吞素与 Dynamin-1 以及 Plexin A1 衔接蛋白 CRMP4 的结合。这种控制对于海马神经元中轴突伸长、分支和生长锥形成是必需的。激酶还通过 Bin1 阻止 Dynein 招募到 FEME 载体上。由于 GSK3β 与内吞素结合，它对 FEME 进行局部调节。因此，Cdk5 和 GSK3β 是 FEME 的关键调节因子，只有在它们的活性较低时，才能通过该途径许可细胞进行快速摄取。
