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J. Biol. Chem., Vol. 277, Issue 22, 19882-19888, May 31, 2002
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From the INSERM, Unité 388, Institut L. Bugnard, CHU
Rangueil, 31403 Toulouse Cedex 4, France
We have investigated the mechanisms whereby
2B-Adrenergic Receptor Activates MAPK via a
Pathway Involving Arachidonic Acid Metabolism, Matrix
Metalloproteinases, and Epidermal Growth Factor Receptor
Transactivation*
2B-adrenergic receptor (2B-AR)
promotes MAPK activation in a clone of the renal tubular cell line,
LLC-PK1, transfected with the rat nonglycosylated 2-AR gene. Treatment of LLC-PK1-2B
with UK14304 or dexmedetomidine caused arachidonic acid (AA) release
and ERK2 phosphorylation. AA release was abolished by prior treatment
of the cells with pertussis toxin, quinacrine, or methyl arachidonyl
fluorophosphonate but not by the addition of the MEK inhibitor U0126.
The effects of 2-agonists on MAPK phosphorylation were
mimicked by cell exposure to exogenous AA. On the other hand,
quinacrine abolished the effects of UK14304, but not of AA, suggesting
that AA released through PLA2 is responsible for MAPK activation by
2B-AR. The effects of 2-agonists or AA
were PKC-independent and were attenuated by indomethacin and
nordihydroguaiaretic acid. Treatment with batimastat, CRM 197, or
tyrphostin AG1478 suppressed MAPK phosphorylation promoted by
2-agonist or AA. Furthermore, conditioned culture medium
from UK14304-treated LLC-PK1-2B induced MAPK
phosphorylation in wild-type LLC-PK1. Based on these data, we propose a
model whereby activation of MAPK by 2B-AR is mediated
through stimulation of PLA2, AA release, generation of AA derivatives,
activation of matrix metalloproteinases, release of heparin-binding
EGF-like growth factor, transactivation of epidermal growth factor
receptor, and recruitment of Shc. Whether this pathway is particular to 2B-AR and LLC-PK1 or whether it can be extended to other
cell types and/or other G-protein-coupled receptors remains to be established.
*
This work was supported by the BIOMED 2 Program PL963373
(European Commission, Brussels, Belgium) and by a grant from the Fondation pour la Recherche Médicale (Paris, France).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.
To whom correspondence should be addressed: INSERM Unit 388, Institut Louis Bugnard, CHU Rangueil, Bat. L3, 31403 Toulouse Cedex 4, France. Tel.: 33-561-32-30-90; Fax: 33-562-17-25-54; E-mail:
paris@toulouse.inserm.fr.
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