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J. Biol. Chem., Vol. 275, Issue 37, 29153-29161, September 15, 2000
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From the The rat pheochromocytoma cell line PC12 is
extensively used as a model for studies of neuronal cell
differentiation. These cells develop a sympathetic neuron-like
phenotype when cultured in the presence of nerve growth factor. The
present study was performed in order to assess the role of mouse
GTK (previously named BSK/IYK), a cytoplasmic tyrosine kinase belonging
to the Src family, for neurite outgrowth in PC12 cells. We report that PC12 cells stably overexpressing GTK exhibit a larger fraction of cells
with neurites as compared with control cells, and this response is not
accompanied by an increased ERK activity. Treatment of the cells with
the MEK inhibitor PD98059 did not reduce the GTK-dependent
increased in neurite outgrowth. GTK expression induces a nerve growth
factor-independent Rap1 activation, probably through altered CrkII
signaling. We observe increased CrkII complex formation with
p130Cas, focal adhesion kinase (FAK), and Shb
in PC12-GTK cells. The expression of GTK also correlates with a
markedly increased content of FAK, phosphorylation of the adaptor
protein Shb, and an association between these two proteins. Transient
transfection of GTK-overexpressing cells with RalGDS-RBD or Rap1GAP,
inhibitors of the Rap1 pathway, reduces the GTK-dependent
neurite outgrowth. These data suggest that GTK participates in a
signaling pathway, perhaps involving Shb, FAK and Rap1, that induces
neurite outgrowth in PC12 cells.
GTK, a Src-related Tyrosine Kinase, Induces Nerve Growth
Factor-independent Neurite Outgrowth in PC12 Cells through
Activation of the Rap1 Pathway
RELATIONSHIP TO Shb TYROSINE PHOSPHORYLATION AND ELEVATED LEVELS
OF FOCAL ADHESION KINASE*
,¶
Department of Medical Cell Biology, Uppsala
University, Uppsala 751 23, Sweden and the § Laboratory
of Physiological Chemistry and Center for Biomedical Genetics, Utrecht
University, Utrecht 3584 CG, The Netherlands
*
This work was supported by the Juvenile Diabetes Foundation
International, the Swedish Medical Research Council Grant 31X-10822, the Swedish Diabetes Association, the Novo-Nordisk Foundation, and the
Family Ernfors Fund.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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