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(Received for publication, February 27, 1997, and in revised form, May 27, 1997)
From the Insulin-like growth factor-I (IGF-I) induces
neuronal differentiation in vitro. In the present study, we
examined the signaling pathway underlying IGF-I-mediated neurite
outgrowth. In SH-SY5Y human neuroblastoma cells, treatment with IGF-I
induced concentration- and time-dependent tyrosine
phosphorylation of the type I IGF receptor (IGF-IR) and extracellular
signal-regulated protein kinases (ERK) 1 and 2. These effects of IGF-I
were blocked by a neutralizing antibody against IGF-IR. Whereas IGF-IR
phosphorylation was observed within 1 min, maximal phosphorylation of
ERKs was not reached for 30 min. Both IGF-IR and ERK phosphorylation
were maintained for at least 24 h. Also, the concentration
dependence of IGF-I-stimulated IGF-IR and ERK tyrosine phosphorylation
paralleled that of IGF-I-mediated neurite outgrowth. We further
examined the role of mitogen-activated protein kinase activation in
IGF-I-stimulated neuronal differentiation using the mitogen-activated
protein kinase/ERK kinase inhibitor PD98059. Whereas PD98059 had no
effect on IGF-IR phosphorylation, PD98059 reduced IGF-I-mediated ERK
tyrosine phosphorylation and ERK phosphorylation of the substrate
Elk-1. PD98059 also produced a parallel reduction of IGF-I-stimulated
neurite outgrowth. Finally, consistent with its ability to block
neuronal differentiation, PD98059 inhibited IGF-I-dependent
changes of GAP-43 and c-myc gene expression. Together these
results suggest that activation of ERKs is essential for
IGF-I-stimulated neuronal differentiation.
Volume 272, Number 34,
Issue of August 22, 1997
pp. 21268-21273
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
,
Department of Neurology and the Neuroscience
Program, University of Michigan, Ann Arbor, Michigan 48109, § Department of Anatomy and Cell Biology, State University
of New York Health Science Center, Syracuse, New York 13210, and
¶ Department of Signal Transduction, Parke-Davis Pharmaceutical
Research Division, Warner-Lambert Company,
Ann Arbor, Michigan 48105
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