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

Robert Grosse, Susanne Roelle, Andreas Herrlich, Julia Höhn, Thomas Gudermann

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Gonadotropin releasing hormone (GnRH) contributes to the maintenance of gonadotrope 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 receptor expression is regulated in a β-arrestin-independent fashion, it represents a good model to systematically dissect underlying signaling pathways. In αT3-1 gonadotropes endogenously expressing the GnRH receptor, GnRH challenge resulted in a rapid increase in ERK activity which was attenuated by the epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitor AG1478. In COS-7 cells transiently expressing the human GnRH receptor, agonist-induced ERK activation was independent of free Gβγ subunits but could be mimicked by short-term phorbol ester treatment. Most notably, G(q/11)induced ERK activation was sensitive to N17-Ras and to expression of the C-terminal Src kinase but also to other dominant negative mutants of signaling components localized upstream of Ras, like Shc and the EGFR. GnRH as well as phorbol esters led to Ras activation in COS-7 and αT3- 1 cells, which was dependent on Src and EGFR tyrosine kinases, indicating that both tyrosine kinases act downstream of protein kinase C (PKC) and upstream of Ras. However, Src did not contribute to Shc tyrosine phosphorylation. GnRH or phorbol ester challenge resulted in PKC-dependent EGFR autophosphorylation. Furthermore, a 5-min phorbol ester treatment was sufficient to trigger tyrosine phosphorylation of the platelet-derived growth factor-β receptor in L cells. Thus, in several cell systems PKC is able to stimulate Ras via activation of receptor tyrosine kinases.

Original languageEnglish
Pages (from-to)12251-12260
Number of pages10
JournalJournal of Biological Chemistry
Volume275
Issue number16
DOIs
StatePublished - Apr 21 2000
Externally publishedYes

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