GAP-43 regulates NCAM-180-mediated neurite outgrowth.
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.
Korshunova
Irina
I
Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, DK-2200 Copenhagen, Denmark. irina@plab.ku.dk
Novitskaya
Vera
V
Kiryushko
Darya
D
Pedersen
Nina
N
Kolkova
Kateryna
K
Kropotova
Ekaterina
E
Mosevitsky
Mark
M
Rayko
Mikhail
M
Morrow
John S
JS
Ginzburg
Irith
I
Berezin
Vladimir
V
Bock
Elisabeth
E
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
D004791:Enzyme Inhibitors; D019922:GAP-43 Protein; D019006:Neural Cell Adhesion Molecules; D049452:Green Fluorescent Proteins