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Growth Factor Receptor / Calmodulin-Dependent Transactivation of Epidermal 2 + Activation Is Mediated by Ca Regulated Protein Kinase − Induced Extracellular Signal − Angiotensin II Type 1 Receptor
| Content Provider | Semantic Scholar |
|---|---|
| Author | Tanaka, Yohko Inada, Mitsuo Maruyama, Katsuya Moriguchi, Yasutaka |
| Copyright Year | 1998 |
| Abstract | The signaling cascade elicited by angiotensin II (Ang II) resembles that characteristic of growth factor stimulation, and recent evidence suggests that G protein–coupled receptors transactivate growth factor receptors to transmit mitogenic effects. In the present study, we report the involvement of epidermal growth factor receptor (EGF-R) in Ang II–induced extracellular signal–regulated kinase (ERK) activation, cfosgene expression, and DNA synthesis in cardiac fibroblasts. Ang II induced a rapid tyrosine phosphorylation of EGF-R in association with phosphorylation of Shc protein and ERK activation. Specific inhibition of EGF-R function by either a dominant-negative EGF-R mutant or selective tyrphostin AG1478 completely abolished Ang II–induced ERK activation. Induction of cfos gene expression and DNA synthesis were also abolished by the inhibition of EGF-R function. Calmodulin or tyrosine kinase inhibitors, but not protein kinase C (PKC) inhibitors or downregulation of PKC, completely abolished transactivation of EGF-R by Ang II or the Ca 21 ionophore A23187. Epidermal growth factor (EGF) activity in concentrated supernatant from Ang II–treated cells was not detected, and saturation of culture media with anti-EGF antibody did not affect the Ang II–induced transactivation of EGF-R. Conditioned media in which cells were incubated with Ang II could not induce phosphorylation of EGF-R on recipient cells. Platelet-derived growth factorb receptor was not phosphorylated on Ang II stimulation, and Ang II–induced cjun gene expression was not affected by tyrphostin AG1478. Our results demonstrated that in cardiac fibroblasts Ang II–induced ERK activation and its mitogenic signals are dominantly mediated by EGF-R transactivated in a Ca /calmodulin-dependent manner and suggested that the effects of Ang II on cardiac fibroblasts should be interpreted in association with the signaling pathways regulating cellular proliferation and/or differentiation by growth factors. (Circ Res. 1998;82:1338-1348.) |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://circres.ahajournals.org/content/82/12/1338.full.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
