title: GAP-43 regulates NCAM-180-mediated neurite outgrowth.
abstract: The neural cell adhesion molecule (NCAM), and the growth-associated protein (GAP-43), play pivotal roles in neuronal development and plasticity and possess interdependent functions. However, the mechanisms underlying the functional association of GAP-43 and NCAM have not been elucidated. In this study we show that (over)expression of GAP-43 in PC12E2 cells and hippocampal neurons strongly potentiates neurite extension, both in the absence and in the presence of homophilic NCAM binding. This potentiation is crucially dependent on the membrane association of GAP-43. We demonstrate that phosphorylation of GAP-43 by protein kinase C (PKC) as well as by casein kinase II (CKII) is important for the NCAM-induced neurite outgrowth. Moreover, our results indicate that in the presence of GAP-43, NCAM-induced neurite outgrowth requires functional association of NCAM-180/spectrin/GAP-43, whereas in the absence of GAP-43, the NCAM-140/non-receptor tyrosine kinase (Fyn)-associated signaling pathway is pivotal. Thus, expression of GAP-43 presumably acts as a functional switch for NCAM-180-induced signaling. This suggests that under physiological conditions, spatial and/or temporal changes of the localization of GAP-43 and NCAM on the cell membrane may determine the predominant signaling mechanism triggered by homophilic NCAM binding: NCAM-180/spectrin-mediated modulation of the actin cytoskeleton, NCAM-140-mediated activation of Fyn, or both.
authors.affiliation: Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, DK-2200 Copenhagen, Denmark. irina@plab.ku.dk
authors.forename: Irina
authors.initials: I
authors.lastname: Korshunova
authors.forename: Vera
authors.initials: V
authors.lastname: Novitskaya
authors.forename: Darya
authors.initials: D
authors.lastname: Kiryushko
authors.forename: Nina
authors.initials: N
authors.lastname: Pedersen
authors.forename: Kateryna
authors.initials: K
authors.lastname: Kolkova
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Kropotova
authors.forename: Mark
authors.initials: M
authors.lastname: Mosevitsky
authors.forename: Mikhail
authors.initials: M
authors.lastname: Rayko
authors.forename: John S
authors.initials: JS
authors.lastname: Morrow
authors.forename: Irith
authors.initials: I
authors.lastname: Ginzburg
authors.forename: Vladimir
authors.initials: V
authors.lastname: Berezin
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bock
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts; D019922:GAP-43 Protein / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D016296:Mutagenesis / Q000502:physiology; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology*; D051381:Rats; D013574:Synaptosomes / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D004791:Enzyme Inhibitors; D019922:GAP-43 Protein; D019006:Neural Cell Adhesion Molecules; D049452:Green Fluorescent Proteins