Transactivation of Epidermal Growth Factor Receptor by a 1 A-Adrenoceptor Is Mediated by Phosphatidylinositol 3-Kinase Independently of Activation of Extracellular Signal Regulated Kinases 1 / 2 and Serine-Threonine Kinases in Chinese Hamster Ovary Cells s

Content Provider	Semantic Scholar
Author	Ulu, Nadir Henning, Robert H. Guner, Sahika Zoto, Teuta Duman-Dalkilic, Basak Duin, Marry Gurdal, Hakan
Copyright Year	2013
Abstract	Transactivation of epidermal growth factor receptor (EGFR) by a1adrenoceptor (a1-AR) is implicated in contraction and hypertrophy of vascular smooth muscle (VSM). We examine whether all a1-AR subtypes transactivate EGFR and explore the mechanism of transactivation. Chinese hamster ovary (CHO) cells stably expressing one subtype of a1-AR were transiently transfected with EGFR. The transactivation mechanism was examined both by coexpression of a chimeric erythropoietin (EPO)-EGFR with an extracellular EPO and intracellular EGFR domain, and by pharmacologic inhibition of external and internal signaling routes. All three a1-AR subtypes transactivated EGFR, which was dependent on the increase in intracellular calcium. The EGFR kinase inhibitor AG1478 [4-(39-chloroanilino)-6,7-dimethoxyquinazoline] abrogated a1A-AR and a1D-AR induced phosphorylation of EGFR, but both the inhibition of matrix metalloproteinases by GM6001 [(R)-N4-hydroxy-N-[(S)-2-(1H-indol-3-yl)-1-methylcarbamoylethyl]-2-isobutyl-succinamide] or blockade of EGFRby cetuximab did not. Stimulation of a1A-AR and a1D-AR also induced phosphorylation of EPO-EGFR chimeric receptors. Moreover, a1A-AR stimulation enhanced phosphorylation of extracellular signal regulated kinase (ERK) 1/2 and serine-threonine kinases (Akt), which were both unaffected by AG1478, indicating that ERK1/2 and Akt phosphorylation is independent of EGFR transactivation. Accordingly, inhibitors of ERK1/2 or Akt did not influence the a1A-AR–mediated EGFR transactivation. Inhibition of calcium/ calmodulin-dependent kinase II (CaMKII), phosphatidylinositol 3kinase (PI3K), and Src, however, did block EGFR transactivation by a1A-AR and a1D-AR. These findings demonstrate that all a1-AR subtypes transactivate EGFR, which is dependent on an intracellular signaling route involving an increase in calcium and activation of CaMKII, PI3K, and Src, but not the of ERK1/2 and Akt pathways.
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://jpet.aspetjournals.org/content/jpet/347/1/47.full.pdf
Alternate Webpage(s)	http://jpet.aspetjournals.org/content/jpet/347/1/47.full.pdf?with-ds=yes
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article