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J. Biol. Chem., Vol. 277, Issue 36, 32490-32497, September 6, 2002
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From the Institute of Pharmacology, University of Vienna,
Währinger Strasse 13a, A-1090 Vienna, Austria
The small G protein RAP1 and the kinase B-RAF
have been proposed to link elevations of cAMP to activation of
ERK/mitogen-activated protein (MAP) kinase. In order to delineate
signaling pathways that link receptor-generated cAMP to the activation
of MAP kinase, the human A2A-adenosine
receptor, a prototypical Gs-coupled receptor, was
heterologously expressed in Chinese hamster ovary cells (referred as
CHO-A2A cells). In CHO-A2A cells, the
stimulation of the A2A-receptor resulted in an activation
of RAP1 and formation of RAP1-B-RAF complexes. However, overexpression
of a RAP1 GTPase-activating protein (RAP1GAP), which efficiently
clamped cellular RAP1 in the inactive GDP-bound form, did not affect
A2A-agonist-mediated MAP kinase stimulation. In contrast,
the inhibitor of protein kinase A H89 efficiently suppressed
A2A-agonist-mediated MAP kinase stimulation. Neither
dynamin-dependent receptor internalization nor
receptor-promoted shedding of matrix-bound growth factors accounted for
A2A-receptor-dependent MAP kinase activation.
PP1, an inhibitor of SRC family kinases, blunted both the
A2A-receptor- and the forskolin-induced MAP kinase
stimulation (IC50 = 50 nM); this was also seen
in PC12 cells, which express the A2A-receptor endogenously,
and in NIH3T3 fibroblasts, in which cAMP causes MAP kinase stimulation.
In the corresponding murine fibroblast cell line SYF, which lacks the
ubiquitously expressed SRC family kinases SRC, YES, and FYN, forskolin
barely stimulated MAP kinase; this reduction was reversed in cells in
which c-SRC had been reintroduced. These findings show that activation
of MAP kinase by cAMP requires a SRC family kinase that lies downstream
of protein kinase A. A role for RAP1, as documented for the
MAP Kinase Stimulation by cAMP Does Not Require RAP1 but SRC
Family Kinases*
,
2-adrenergic receptor, is apparently contingent on
receptor endocytosis.
*
This work was supported by Science Foundation of the
Austrian National Bank Grant 8520 and Austrian Science
Foundation Grant P15306).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.
Present address: Dept. of Surgery, University of Vienna,
Währinger Gürtel 18-20, A-1090 Vienna.
§
Present address: St. Anna Kinderspital, Kinderspitalgasse 6; A-1090
Vienna, Austria.
¶
To whom correspondence should be addressed: Institute of
Pharmacology, Vienna University; Währinger Str. 13a, A-1090
Vienna; Austria. Tel.: 43-1-4277-64171; Fax: 43-1-4277-9641;
E-mail: michael. freissmuth@univie.ac.at.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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