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J. Biol. Chem., Vol. 277, Issue 46, 43623-43630, November 15, 2002
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From the In PC12 cells, a well studied model for neuronal
differentiation, an elevation in the intracellular cAMP level increases
cell survival, stimulates neurite outgrowth, and causes activation of
extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). Here we
show that an increase in the intracellular cAMP concentration induces
tyrosine phosphorylation of two receptor tyrosine kinases, i.e. the epidermal growth factor (EGF) receptor and the
high affinity receptor for nerve growth factor (NGF), also termed
TrkA. cAMP-induced tyrosine phosphorylation of the EGF
receptor is rapid and correlates with ERK1/2 activation. It occurs also
in Panc-1, but not in human mesangial cells. cAMP-induced tyrosine
phosphorylation of the NGF receptor is slower and correlates with
Akt activation. Inhibition of EGF receptor tyrosine
phosphorylation, but not of the NGF receptor, reduces cAMP-induced
neurite outgrowth. Expression of dominant-negative Akt does not
abolish cAMP-induced survival in serum-free media, but increases
cAMP-induced ERK1/2 activation and neurite outgrowth. Together,
our results demonstrate that cAMP induces dual signaling in PC12 cells:
transactivation of the EGF receptor triggering the ERK1/2 pathway and
neurite outgrowth; and transactivation of the NGF receptor promoting
Akt activation and thereby modulating ERK1/2 activation and neurite outgrowth.
Cyclic AMP Induces Transactivation of the Receptors for
Epidermal Growth Factor and Nerve Growth Factor, Thereby Modulating
Activation of MAP Kinase, Akt, and Neurite Outgrowth in PC12
Cells*
§,
,,,,, and
Department of Internal Medicine and
Institute for Biochemistry II, Johann
Wolfgang Goethe-University, D-60590 Frankfurt, Germany,
¶ Ludwig Institute for Cancer Research, S-75124 Uppsala,
Sweden, Department of Internal Medicine I, University of
Ulm, D-89070 Ulm, Germany, and ** Aventis Pharma
Deutschland GmbH, D-65812 Bad Soden, Germany
*
This work was partly supported by grants from the Deutsche
Forschungsgemeinschaft (Ze 237/4-3 and SFB 518-A5) and the University of Frankfurt (Nachlass Held/Hecker).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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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