| 11566906 |
Shibasaki Y, Matsubara H, Nozawa Y, Mori Y, Masaki H, Kosaki A, Tsutsumi Y, Uchiyama Y, Fujiyama S, Nose A, Iba O, Tateishi E, Hasegawa T, Horiuchi M, Nahmias C, Iwasaka T: Angiotensin II type 2 receptor inhibits epidermal growth factor receptor transactivation by increasing association of SHP-1 tyrosine phosphatase. Hypertension. 2001 Sep;38(3):367-72.
Angiotensin (Ang) II has 2 major receptor isoforms, Ang type 1 (AT (1)) and Ang type (AT (2)). AT (1) transphosphorylates epidermal growth factor receptor (EGFR) to activate extracellular signal-regulated kinase (ERK). Although AT (2) was shown to inactivate ERK, the action of AT (2) on EGFR activation remains undefined. Using AT (2)-overexpressing vascular smooth muscle cells from AT (2) transgenic mice, we studied these undefined actions of AT (2). Maximal ERK activity induced by Ang II was increased 1.9- and 2.2-fold by AT (2) inhibition, which was abolished by orthovanadate but not okadaic acid or pertussis toxin. AT (2) inhibited AT (1)-mediated EGFR tyrosine phosphorylation by 63%. The activity of SHP-1 tyrosine phosphatase was significantly upregulated 1 minute after AT (2) stimulation and association of SHP-1 with EGFR was increased, whereas AT (2) failed to tyrosine phosphorylate SHP-1. Stable overexpression of SHP-1-dominant negative mutant completely abolished AT (2)-mediated inhibition of EGFR and ERK activation. AT (1)-mediated c-fos mRNA accumulation was attenuated by 48% by AT (2) stimulation. Induction of fibronectin gene containing an AP-1 responsive element in its 5'-flanking region was decreased by 37% after AT (2) stimulation, corresponding to the results of gel mobility assay with the AP-1 sequence of fibronectin as a probe. These findings suggested that AT (2) inhibits ERK activity by inducing SHP-1 activity, leading to decreases in AP-1 activity and AP-1-regulated gene expression, in which EGFR dephosphorylation plays an important role via association of SHP-1. |
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