Epidermal growth factor receptor tyrosine kinase mediates Ras activation by gonadotropin-releasing hormone

Citation
R. Grosse et al., Epidermal growth factor receptor tyrosine kinase mediates Ras activation by gonadotropin-releasing hormone, J BIOL CHEM, 275(16), 2000, pp. 12251-12260
Citations number
57
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
275
Issue
16
Year of publication
2000
Pages
12251 - 12260
Database
ISI
SICI code
0021-9258(20000421)275:16<12251:EGFRTK>2.0.ZU;2-B
Abstract
Gonadotropin releasing hormone (GnRH) contributes to the maintenance of gon adotrope function by increasing extracellular signal-regulated kinase (ERK) activity subsequent to binding to its cognate G-protein-coupled receptor. As the GnRH receptor exclusively interacts with G(q/11) proteins and as rec eptor expression is regulated in a beta-arrestin-independent fashion, it re presents a good model to systematically dissect underlying signaling pathwa ys. In alpha T3-1 gonadotropes endogenously expressing the GnRH receptor, G nRH challenge resulted in a rapid increase in ERK activity which was attenu ated by the epidermal growth factor receptor (EGFR)-specific tyrosine kinas e inhibitor AG1478, In COS-7 cells transiently expressing the human GnRH re ceptor, agonist-induced ERK activation was independent of free G beta gamma subunits but could be mimicked by shortterm phorbol ester treatment. Most notably, G(q/11)-induced ERR activation was sensitive to N17-Ras and to exp ression of the C-terminal Src kinase but also to other dominant negative mu tants of signaling components localized upstream of Ras, like Shc and the E GFR. GnRH as well as phorbol esters led to Ras activation in COS-7 and alph a T3-1 cells, which was dependent on Src and EGFR tyrosine kinases, indicat ing that both tyrosine kinases act downstream of protein kinase C (PHC) and upstream of Ras, However, Src did not contribute to Shc tyrosine phosphory lation, GnRH or phorbol ester challenge resulted in PKC-dependent EGFR auto phosphorylation, Furthermore, a 5-min phorbol ester treatment was sufficien t to trigger tyrosine phosphorylation of the platelet-derived growth factor -beta receptor in L cells, Thus, in several cell systems PKC is able to sti mulate Ras via activation of receptor tyrosine kinases.