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

Biochem Biophys Res Commun. 2001 Apr 20;282(5):1085-91. doi: 10.1006/bbrc.2001.4695.

Abstract

Angiotensin II (Ang II) has two major receptor isoforms, AT1 and AT2. AT1 transphosphorylates Ca(2+)-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.

MeSH terms

  • Angiotensin Receptor Antagonists
  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Focal Adhesion Kinase 2
  • Genes, Dominant
  • Intracellular Fluid / metabolism
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / metabolism*
  • Phosphorylation / drug effects
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • RNA, Messenger / metabolism
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin / genetics
  • Receptors, Angiotensin / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Vanadates / pharmacology

Substances

  • Angiotensin Receptor Antagonists
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin
  • Vanadates
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 2
  • Ptk2b protein, mouse
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn6 protein, mouse
  • Calcium