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The Journal of Neuroscience, March 15, 2000, 20(6):2238-2246
Neural Cell Adhesion Molecule-Stimulated Neurite Outgrowth
Depends on Activation of Protein Kinase C and the
Ras-Mitogen-Activated Protein Kinase Pathway
Kateryna
Kolkova,
Vera
Novitskaya,
Nina
Pedersen,
Vladimir
Berezin, and
Elisabeth
Bock
Protein Laboratory, Institute of Molecular Pathology, University of
Copenhagen, DK-2200, Copenhagen N, Denmark
The signal transduction pathways associated with neural cell
adhesion molecule (NCAM)-induced neuritogenesis are only partially characterized. We here demonstrate that NCAM-induced neurite outgrowth depends on activation of p59fyn, focal
adhesion kinase (FAK), phospholipase C (PLC), protein kinase C
(PKC), and the Ras-mitogen-activated protein (MAP) kinase pathway.
This was done using a coculture system consisting of PC12-E2 cells
grown on fibroblasts, with or without NCAM expression, allowing
NCAM-NCAM interactions resulting in neurite outgrowth. PC12-E2 cells
were transiently transfected with expression plasmids encoding
constitutively active forms of Ras, Raf, MAP kinase kinases MEK1 and 2, dominant negative forms of Ras and Raf, and the FAK-related nonkinase.
Alternatively, PC12-E2 cells were submitted to treatment with
antibodies to the fibroblast growth factor (FGF) receptor, inhibitors
of the nonreceptor tyrosine kinase
p59fyn, PLC, PKC and MEK and an activator
of PKC, phorbol-12-myristate-13-acetate (PMA). MEK2 transfection
rescued cells treated with all inhibitors. The same was found for PMA
treatment, except when cells concomitantly were treated with the MEK
inhibitor. Arachidonic acid rescued cells treated with antibodies to
the FGF receptor or the PLC inhibitor, but not cells in which the
activity of PKC, p59fyn, FAK, Ras, or MEK
was inhibited. Interaction of NCAM with a synthetic NCAM peptide
ligand, known to induce neurite outgrowth, was shown to stimulate
phosphorylation of the MAP kinases extracellular signal-regulated
kinases ERK1 and ERK2. The MAP kinase activation was sustained,
because ERK1 and ERK2 were phosphorylated in PC12-E2 cells and primary
hippocampal neurons even after 24 hr of cultivation on NCAM-expressing
fibroblasts. Based on these results, we propose a model of NCAM
signaling involving two pathways: NCAM-Ras-MAP kinase and NCAM-FGF
receptor-PLC-PKC, and we propose that PKC serves as the link
between the two pathways activating Raf and thereby creating the
sustained activity of the MAP kinases necessary for neuronal differentiation.
Key words:
NCAM; Ras-MAP kinase pathway; neurite outgrowth; PKC; MAP kinase activation; FGF receptor
Copyright © 2000 Society for Neuroscience 0270-6474/00/2062238-09$05.00/0
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