Recycling pathway of L1

L1 functions in many aspects of neuronal development including axon outgrowth and neuronal migration. These functions require coordination between L1 and the actin cytoskeleton. F-actin continuously moves in a retrograde direction from the P-(peripheral) domain of the growth cone towards the growth cone's C-(central) domain. L1, attached to the actin cytoskeleton via membrane cytoskeletal linkers (MCKs) such as ankyrins (Ankyrin-G, -B and -R) and members of the ERMs (ezrin, radixin, and moesin) family, link this retrograde F-actin flow with extracellular immobile ligands.<br>Forward translocation of growth cone requires not only the CAM-actin linkage but also a gradient of cell substrate adhesion (strong adhesion at the front and weak adhesion at the rear) so that the cytoskeletal machinery is able to pull the cell forward as attachments at the rear are released. This asymmetry is achieved in part by internalizing L1 molecules as they are moved to the rear of the growth cone coupled to retrograde F-actin flow and recycling them to the leading edge plasma membrane.<br>L1 internalization is mediated by phosphorylation and dephosphorylation. The L1 cytoplasmic domain (L1CD) carries an endocytic or sorting motif, YRSLE, that is recognized by the clathrin associated adaptor protein-2 (AP-2). AP-2 binds the YRSLE motif only when its tyrosine is not phosphorylated and triggers L1 endocytosis. SRC kinase associated with lipid rafts in the P-domain membrane phosphorylates L1 molecules on tyrosine-1176, stabilizing them in the plasma membrane. L1 endocytosis is triggered by the dephosphorylation of Y1176 within the C domain. Some of these internalized L1 molecules are transported in an anterograde direction along microtubules for reuse in the leading edge.

L1 函数在神经元发育的多个方面发挥重要作用，包括轴突生长和神经元迁移。这些功能需要 L1 与肌动蛋白细胞骨架之间的协调。F-肌动蛋白从生长锥的 P-(外围) 区域向 C-(中心) 区域持续逆向移动。L1 通过膜细胞骨架连接子（如锚蛋白G、B 和 R 以及 ERM 家族成员）与肌动蛋白细胞骨架相连，将这种逆向的 F-肌动蛋白流动与细胞外静止配体相连接。<br>生长锥的前向转运不仅需要 CAM-肌动蛋白连接，还需要细胞底物粘附梯度（前端强粘附，后端弱粘附），以便细胞骨架机制能够将细胞向前拉动，同时释放后端的附着物。这种不对称性部分是通过将 L1 分子内化来实现的，这些分子在逆向 F-肌动蛋白流动的作用下被移至生长锥的后端，并重新循环至前沿的质膜。<br>L1 的内化通过磷酸化和去磷酸化介导。L1 的细胞质域（L1CD）携带一个内吞或分类基序 YRSLE，该基序被 clathrin 相关适配蛋白-2（AP-2）识别。AP-2 仅在其酪氨酸未磷酸化时才结合 YRSLE 基序，并触发 L1 的内吞。与 P 区域膜中的脂筏结合的 SRC 酪氨酸激酶在酪氨酸-1176 位点磷酸化 L1 分子，使其在质膜中稳定。L1 的内吞由 C 域内 Y1176 的去磷酸化触发。其中一些内化的 L1 分子沿着微管向前进方向运输，以便在前沿再次使用。