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(Hypertension. 2001;38:367.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Angiotensin II Type 2 Receptor Inhibits Epidermal Growth Factor Receptor Transactivation by Increasing Association of SHP-1 Tyrosine Phosphatase

Yasunobu Shibasaki; Hiroaki Matsubara; Yoshihisa Nozawa; Yasukiyo Mori; Hiroya Masaki; Atsushi Kosaki; Yoshiaki Tsutsumi; Yoko Uchiyama; Soichiro Fujiyama; Atsuko Nose; Osamu Iba; Eriko Tateishi; Takamasa Hasegawa; Masatsugu Horiuchi; Clara Nahmias; Toshiji Iwasaka

From the Department of Medicine II, Kansai Medical University (Y.S., H. Matsubara, Y.M., H. Masaki, A.K., Y.T., Y.U., S.F., A.N., O I., E.T., T.H., T.I.), Moriguchi, Osaka, Japan; Pharmacological Laboratory, Taiho Pharmaceutical Co Ltd (Y.N.), Tokushima, Japan; Department of Medical Biochemistry, Ehime University School of Medicine (M.H.), Ehime, Japan; and Institut Cochin de Genetique Moleculaire, Centre Nattionale de Recherche Scientifique (C.N.), Paris, France.

Correspondence to Hiroaki Matsubara, MD, PhD, Department of Medicine II, Kansai Medical University, Fumizonocho 10-15, Moriguchi, Osaka 570-8507, Japan. E-mail matsubah{at}takii.kmu.ac.jp

Abstract—— Angiotensin (Ang) II has 2 major receptor isoforms, Ang type 1 (AT₁) and Ang type (AT₂). AT₁ transphosphorylates epidermal growth factor receptor (EGFR) to activate extracellular signal–regulated kinase (ERK). Although AT₂ was shown to inactivate ERK, the action of AT₂ on EGFR activation remains undefined. Using AT₂-overexpressing vascular smooth muscle cells from AT₂ transgenic mice, we studied these undefined actions of AT₂. Maximal ERK activity induced by Ang II was increased 1.9- and 2.2-fold by AT₂ inhibition, which was abolished by orthovanadate but not okadaic acid or pertussis toxin. AT₂ inhibited AT₁-mediated EGFR tyrosine phosphorylation by 63%. The activity of SHP-1 tyrosine phosphatase was significantly upregulated 1 minute after AT₂ stimulation and association of SHP-1 with EGFR was increased, whereas AT₂ failed to tyrosine phosphorylate SHP-1. Stable overexpression of SHP-1–dominant negative mutant completely abolished AT₂-mediated inhibition of EGFR and ERK activation. AT₁-mediated c-fos mRNA accumulation was attenuated by 48% by AT₂ stimulation. Induction of fibronectin gene containing an AP-1 responsive element in its 5'-flanking region was decreased by 37% after AT₂ stimulation, corresponding to the results of gel mobility assay with the AP-1 sequence of fibronectin as a probe. These findings suggested that AT₂ 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.

Key Words: angiotensin II • angiotensin II receptors • angiotensin II type 2 receptor • tyrosinephosphatase • SHP-1 • epidermal growth factor receptor

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