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
| Autor: | Ben Storie, Brenda Litchie, Peter Zahradka, Gail Helwer |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Transcriptional Activation
medicine.medical_specialty Angiotensin receptor Swine Myocytes Smooth Muscle Biology Tropomyosin receptor kinase C Antibodies Receptor Angiotensin Type 1 Receptor tyrosine kinase Receptor IGF Type 1 Phosphatidylinositol 3-Kinases Endocrinology Cell Movement Internal medicine medicine Animals Enzyme Inhibitors Insulin-Like Growth Factor I Phosphorylation Cells Cultured Angiotensin II receptor type 1 Angiotensin II Protein-Tyrosine Kinases Enzyme Activation src-Family Kinases Interleukin-21 receptor ROR1 biology.protein Mitogen-Activated Protein Kinases hormones hormone substitutes and hormone antagonists Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Endocrinology. 145:2978-2987 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2004-0029 |
| Popis: | 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 p70S6K 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. |
| Databáze: | OpenAIRE |
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