Role of tyrosine kinase receptors in angiotensin II AT2 receptor signaling: involvement in neurite outgrowth and in p42/p44mapk activation in NG108-15 cells.
NG108-15 cells, which have a rounding-up morphology when cultured in serum-supplemented medium, extend neurites when stimulated for 3 d with angiotensin II (Ang II). The aim of the present study was to investigate whether growth factor receptors are necessary for mediating the effects of Ang II. A 3-d treatment with AG879, an inhibitor of nerve growth factor receptor TrkA, strongly affected neurite outgrowth and phosphorylation of p42/p44(mapk) induced by Ang II. PD168393, an inhibitor of epidermal growth factor (EGF) receptor slightly decreased Ang II-induced neurite outgrowth, whereas AG213, an inhibitor of both platelet-derived growth factor receptor and EGF receptor, stimulated neurite outgrowth and p42/p44(mapk) phosphorylation on its own, without affecting further stimulation with Ang II. Moreover, Ang II induced the phosphorylation of TrkA (maximum at 5 min of incubation in the presence of serum or at 20 min in cells depleted in serum for 2 h) and a rapid increase in Rap1 activity, both effects abolished in cells preincubated with 10 microm AG879. In summary, the present results demonstrate that AT(2) receptor-induced sustained activation of p42/p44(mapk) and corresponding neurite outgrowth are mediated by phosphorylation of the nerve growth factor TrkA receptor. However, the results also point out that the presence of other growth factors, such as EGF or PDFG, may interfere with the effect of Ang II. Altogether, the current findings clearly indicate that the effects of the AT(2) receptor on neurite outgrowth dynamics are modulated by the presence of growth factors in the culture medium.
Plouffe
Bianca
B
Service of Endocrinology, and Department of Physiology and Biophysics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4.
Guimond
Marie-Odile
MO
Beaudry
Hélène
H
Gallo-Payet
Nicole
N
D000804:Angiotensin II / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D006801:Humans; D008870:Microtubules / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D009414:Nerve Growth Factors / Q000494:pharmacology; D016501:Neurites / Q000502:physiology*; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000502:physiology
D009414:Nerve Growth Factors; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D020794:Receptor Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020827:rap1 GTP-Binding Proteins