PathwayStep6233 PathwayStep6232 PathwayStep6231 PathwayStep6230 PathwayStep6237 PathwayStep6236 PathwayStep6235 PathwayStep6234 PathwayStep6238 PathwayStep6239 PathwayStep6242 PathwayStep6241 PathwayStep6243 PathwayStep6240 Recycling pathway of L1 Authored: Garapati, P V, 2008-07-30 10:22:58 Edited: Garapati, P V, 2008-07-30 10:22:58 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. Pubmed10804209 Pubmed11717353 Pubmed14709786 Reactome Database ID Release 43437239 Reactome, http://www.reactome.org ReactomeREACT_22365 Reviewed: Maness, PF, 2010-02-16 L1 binds to AP-2 Clathrin complex Formation of clathrin coated vesicle Shootin-1 links L1 and retrograde actin flow Dephosphorylation of pL1 (Y1176) Interaction of NUMB with L1 Linkage of L1 with treadmilling F-actin L1 trans-homophilic interaction L1 binds ERM family members Phosphorylation of L1 by SRC Phosphorylation of L1 by p90rsk Transport of L1 into endosomes Transport of L1 from C-domain to P-domain Phosphorylation of L1 by ERK Reinsertion of L1 into the plasma membrane