Transactivation of the insulin-like growth factor-I receptor by angiotensin II mediates downstream signaling from the angiotensin II type 1 receptor to phosphatidylinositol 3-kinase

Endocrinology. 2004 Jun;145(6):2978-87. doi: 10.1210/en.2004-0029. Epub 2004 Feb 19.

Abstract

Angiotensin II (AngII) activates phosphatidylinositol 3-kinase (PI3-kinase), a known effector of receptor tyrosine kinases. Treatment of smooth muscle cells with AngII has also been shown to promote phosphorylation of various tyrosine kinase receptors. We therefore investigated the relationship between AngII and IGF-I receptor activation in smooth muscle cells with a phosphorylation-specific antibody. Our experiments showed that IGF-I receptor phosphorylation was maximally stimulated within 10 min by AngII. Inclusion of an IGF-I-neutralizing antibody in the culture media did not prevent IGF-I receptor phosphorylation after AngII treatment, which argues that a paracrine/autocrine loop is not required. Furthermore, this process was blocked by losartan and 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP-1), indicating stimulation of IGF-I receptor phosphorylation occurs via AngII type 1 receptor-dependent activation of Src kinase. The functional significance of IGF-I receptor transactivation was examined with selective inhibitors of the IGF-I receptor kinase (AG1024, AG538). When AngII-treated cells were incubated with AG1024 or AG538, phosphorylation of the regulatory p85 subunit of PI3-kinase was blocked. Furthermore, phosphorylation of the downstream factor p70(S6K) did not occur. In contrast, AG1024 did not prevent MAPK or Src kinase activation by AngII. AG1024 also did not inhibit AngII-dependent cell migration, although this process was blocked by inhibitors of the epidermal growth factor and platelet-derived growth factor receptors. Transactivation of the IGF-I receptor is therefore a critical mediator of PI3-kinase activation by AngII but is not required for stimulation of the MAPK cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology
  • Angiotensin II / physiology*
  • Animals
  • Antibodies / pharmacology
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Insulin-Like Growth Factor I / immunology
  • Mitogen-Activated Protein Kinases / metabolism
  • Myocytes, Smooth Muscle / physiology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Receptor, IGF Type 1 / drug effects
  • Receptor, IGF Type 1 / genetics*
  • Receptor, IGF Type 1 / metabolism
  • Signal Transduction / physiology*
  • Swine
  • Transcriptional Activation / physiology*
  • src-Family Kinases / metabolism

Substances

  • Antibodies
  • Enzyme Inhibitors
  • Receptor, Angiotensin, Type 1
  • Angiotensin II
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Receptor, IGF Type 1
  • src-Family Kinases
  • Mitogen-Activated Protein Kinases