This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shibasaki, Y. Articles by Iwasaka, T. Search for Related Content PubMed PubMed Citation Articles by Shibasaki, Y. Articles by Iwasaka, T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections ACE/Angiotension receptors Cell biology/structural biology Cell signalling/signal transduction Growth factors/cytokines Hypertension - basic studies Smooth muscle proliferation and differentiation Endothelium/vascular type/nitric oxide

(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

This article has been cited by other articles:

				S. Eguchi Triple Twist Theory of Rho Inhibition by the Angiotensin II Type 2 Receptor Circ. Res., May 23, 2008; 102(10): 1143 - 1145. [Full Text] [PDF]

				H. Okada, T. Inoue, T. Kikuta, Y. Watanabe, Y. Kanno, S. Ban, T. Sugaya, M. Horiuchi, and H. Suzuki A Possible Anti-Inflammatory Role of Angiotensin II Type 2 Receptor in Immune-Mediated Glomerulonephritis during Type 1 Receptor Blockade Am. J. Pathol., November 1, 2006; 169(5): 1577 - 1589. [Abstract] [Full Text] [PDF]

				B. Plouffe, M.-O. Guimond, H. Beaudry, and N. Gallo-Payet Role of Tyrosine Kinase Receptors in Angiotensin II AT2 Receptor Signaling: Involvement in Neurite Outgrowth and in p42/p44mapk Activation in NG108-15 Cells Endocrinology, October 1, 2006; 147(10): 4646 - 4654. [Abstract] [Full Text] [PDF]

				M. Phillippe, D. F. Bradley, D. Engle, and L. Sweet SHP Protein Tyrosine Phosphatase Expression in Rat Uterine Tissue Reproductive Sciences, July 1, 2006; 13(5): 338 - 342. [Abstract] [PDF]

				K. Kappert, K. G. Peters, F. D. Bohmer, and A. Ostman Tyrosine phosphatases in vessel wall signaling Cardiovasc Res, February 15, 2005; 65(3): 587 - 598. [Abstract] [Full Text] [PDF]

				E.J. Landon and T. Inagami Beyond the G Protein: The Saga of the Type 2 Angiotensin II Receptor Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 15 - 16. [Full Text] [PDF]

				H. Takeda, Y. Katagata, Y. Hozumi, and S. Kondo Effects of Angiotensin II Receptor Signaling during Skin Wound Healing Am. J. Pathol., November 1, 2004; 165(5): 1653 - 1662. [Abstract] [Full Text] [PDF]

				S. Nouet, N. Amzallag, J.-M. Li, S. Louis, I. Seitz, T.-X. Cui, A.-M. Alleaume, M. Di Benedetto, C. Boden, M. Masson, et al. Trans-inactivation of Receptor Tyrosine Kinases by Novel Angiotensin II AT2 Receptor-interacting Protein, ATIP J. Biol. Chem., July 9, 2004; 279(28): 28989 - 28997. [Abstract] [Full Text] [PDF]

				L. Wu, M. Iwai, Z. Li, T. Shiuchi, L.-J. Min, T.-X. Cui, J.-M. Li, M. Okumura, C. Nahmias, and M. Horiuchi Regulation of Inhibitory Protein-{kappa}B and Monocyte Chemoattractant Protein-1 by Angiotensin II Type 2 Receptor-Activated Src Homology Protein Tyrosine Phosphatase-1 in Fetal Vascular Smooth Muscle Cells Mol. Endocrinol., March 1, 2004; 18(3): 666 - 678. [Abstract] [Full Text] [PDF]

				Y.-H. Feng, Y. Sun, and J. G. Douglas Gbeta gamma -independent constitutive association of Galpha s with SHP-1 and angiotensin II receptor AT2 is essential in AT2-mediated ITIM-independent activation of SHP-1 PNAS, September 17, 2002; 99(19): 12049 - 12054. [Abstract] [Full Text] [PDF]