1. Effect of Angiotensin II Type 2 Receptor on Tyrosine Kinase Pyk2 and c-Jun NH2-Terminal Kinase via SHP-1 Tyrosine Phosphatase Activity: Evidence from Vascular-Targeted Transgenic Mice of AT2 Receptor
- Author
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Atsushi Kosaki, Yasukiyo Mori, Eriko Tateishi, Osamu Iba, Mitsuhiko Okigaki, Soichiro Fujiyama, Hiroaki Matsubara, Toshiji Iwasaka, Yasunobu Shibasaki, Atsuko Nose, Hiroya Masaki, Yoshiaki Tsutsumi, Masatsugu Horiuchi, Takamasa Hasegawa, Yoko Uchiyama, and Clara Nahmias
- Subjects
Intracellular Fluid ,endocrine system ,Biophysics ,Mice, Transgenic ,Mitogen-activated protein kinase kinase ,Receptor, Angiotensin, Type 2 ,Biochemistry ,Tropomyosin receptor kinase C ,Muscle, Smooth, Vascular ,Receptor, Angiotensin, Type 1 ,Receptor tyrosine kinase ,MAP2K7 ,Angiotensin Receptor Antagonists ,Mice ,Animals ,RNA, Messenger ,Enzyme Inhibitors ,Phosphorylation ,Molecular Biology ,Cells, Cultured ,Genes, Dominant ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,Receptors, Angiotensin ,MAP kinase kinase kinase ,biology ,Chemistry ,Protein Tyrosine Phosphatase, Non-Receptor Type 6 ,Intracellular Signaling Peptides and Proteins ,JNK Mitogen-Activated Protein Kinases ,Cell Biology ,Protein-Tyrosine Kinases ,respiratory system ,Cell biology ,Focal Adhesion Kinase 2 ,ROR1 ,cardiovascular system ,Cancer research ,biology.protein ,Calcium ,Mitogen-Activated Protein Kinases ,Protein Tyrosine Phosphatases ,Vanadates ,hormones, hormone substitutes, and hormone antagonists ,Platelet-derived growth factor receptor ,Signal Transduction ,circulatory and respiratory physiology ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Angiotensin II (Ang II) has two major receptor isoforms, AT1 and AT2. AT1 transphosphorylates Ca2+-sensitive tyrosine kinase Pyk2 to activate c-Jun NH2-terminal kinase (JNK). Although AT2 inactivates extracellular signal-regulated kinase (ERK) via tyrosine phosphatases (PTP), the action of AT2 on Pyk2 and JNK remains undefined. Using AT2-overexpressing vascular smooth muscle cells (AT2-VSMC) from AT2-transgenic mice, we studied these undefined actions of AT2. AT1-mediated JNK activity was increased 2.2-fold by AT2 inhibition, which was abolished by orthovanadate. AT2 did not affect AT1-mediated Pyk2 phosphorylation, but attenuated c-Jun mRNA accumulation by 32%. The activity of src-homology 2 domain-containing PTP (SHP-1) was significantly upregulated 1 min after AT2 stimulation. Stable overexpression of SHP-1 dominant negative mutant in AT2-VSMC completely abolished AT2-mediated inhibition of JNK activation and c-Jun expression. These findings suggest that AT2 inhibits JNK activity by affecting the downstream signal of Pyk2 in a SHP-1-dependent manner, leading to a decrease in c-Jun expression.
- Published
- 2001
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