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Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, 39120 Magdeburg, Germany
Protease-activated receptors (PARs), newly
identified members of G protein-coupled receptors, are widely
distributed in the brain. Thrombin evokes multiple cellular responses
in a large variety of cells by activating PAR-1, -3, and -4. In
cultured rat astrocytes we investigated the signaling pathway of
thrombin- and PAR-activating peptide (PAR-AP)-induced cell
proliferation. Our results show that PAR activation stimulates
proliferation of astrocytes through the ERK pathway. Thrombin
stimulates ERK1/2 phosphorylation in a time- and
concentration-dependent manner. This effect can be fully mimicked by a
specific PAR-1-AP but only to a small degree by PAR-3-AP and PAR-4-AP.
PAR-2-AP can induce a moderate ERK1/2 activation as well.
Thrombin-stimulated ERK1/2 activation is mainly mediated by PAR-1 via
two branches: 1) the PTX-sensitive G
protein/(
-subunits)-phosphatidylinositol 3-kinase branch, and
2) the Gq-PLC-(InsP3
receptor)/Ca2+-PKC pathway. Thrombin- or PAR-1-AP-induced
ERK activation is partially blocked by a selective EGF receptor
inhibitor, AG1478. Nevertheless, transphosphorylation of EGF receptor
is unlikely for ERK1/2 activation and is certainly not involved in
PAR-1-induced proliferation. The metalloproteinase mechanism involving
transactivation of the EGF receptor by released heparin-binding EGF was
excluded. EGF receptor activation was detected by the receptor
autophosphorylation site, tyrosine 1068. Our data suggest that
thrombin-induced mitogenic action in astrocytes occurs independently of
EGF receptor transphosphorylation.
protease-activated receptors; extracellular signal-regulated protein kinase; calcium signaling; epidermal growth factor receptor; transactivation; mitogen-activated protein kinase
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