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Articles in PresS, published online ahead of print June 20, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00001.2002
Submitted on January 2, 2002
Accepted on June 18, 2002
1 Institut fur Neurobiochemie, Medizinische Fakultat der Otto-von-Guericke-Universitat Magdeburg, Magdeburg, Germany
* To whom correspondence should be addressed. E-mail: georg.reiser{at}medizin.uni-magdeburg.de.
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. We investigated in cultured rat astrocytes, the signaling pathway of thrombin- and PAR activating peptide (PAR-AP)-induced cell proliferation. Our results demonstrate 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 is capable to induce a moderate ERK1/2 activation as well. Thrombin-stimulated ERK1/2 activation is mainly mediated by PAR-1, via two branches; firstly, the PTX-sensitive G protein/(ß
subunits) - PI 3-kinase branch and secondly, 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 auto phosphorylation site tyrosine 1068. Taken together, our data suggest that thrombin-induced mitogenic action in astrocytes occurs independently of EGF receptor transphosphorylation.
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