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C-Src is Activated by the EGF Receptor in a Pathway that Mediates JNK and ERK Activation by Gonadotropin-Releasing

Sarah Kraus1, Outhiriaradjou Benard1, Zvi Naor2

  • 1Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 7610001, Israel.

International Journal of Molecular Sciences
|November 18, 2020
PubMed

Insights

G-protein-coupled receptor (GPCR) signaling involves mitogen-activated protein kinase (MAPK) cascades. This study reveals a novel GnRH receptor (GnRHR) pathway via Gαi and EGF receptor, activating JNK and ERK signaling.

Area of Science:

  • Cellular signaling pathways
  • Endocrinology and reproductive biology
  • Molecular cell biology

Background:

  • G-protein-coupled receptors (GPCRs) are crucial cell surface receptors involved in diverse physiological processes.
  • Mitogen-activated protein kinase (MAPK) signaling cascades are key downstream effectors of GPCRs, but their precise activation mechanisms remain incompletely understood.
  • The gonadotropin-releasing hormone receptor (GnRHR) is a prototypical GPCR regulating the reproductive system, making it a vital model for studying GPCR signaling.

Purpose of the Study:

  • To elucidate the specific signaling pathways utilized by the gonadotropin-releasing hormone receptor (GnRHR) to activate mitogen-activated protein kinases (MAPKs).
  • To investigate the roles of Gαi, epidermal growth factor receptor (EGFR), and other signaling molecules in GnRHR-mediated MAPK activation.
  • To compare the identified signaling pathways with those observed in other GnRHR-expressing cells, highlighting potential cell-type-specific mechanisms.

Main Methods:

  • Expression of GnRHR in COS7 cells for controlled experimental conditions.
  • Pharmacological and molecular biology techniques to dissect signaling cascades, including assessment of Gαi, EGFR, c-Src, PI3K, Ras, JNK, and ERK activation.
  • Investigation of potential contributions from Gβγ and β-arrestin signaling.

Main Results:

  • GnRHR activates MAPKs primarily through Gαi and the EGF receptor, independent of Hb-EGF and PKCs.
  • A novel pathway for JNK activation involves sequential activation of c-Src and PI3K downstream of the EGF receptor.
  • ERK activation is mediated by the EGF receptor, which activates Ras either directly or via c-Src.

Conclusions:

  • GnRHR utilizes distinct signaling pathways in COS7 cells compared to other cell types, demonstrating GnRH's signaling versatility.
  • The identified pathway, characterized by sequential c-Src and PI3K activation downstream of the EGF receptor, provides a novel model for GnRHR and other GPCR signaling mechanisms.
  • These findings contribute to a deeper understanding of GPCR signal transduction and its implications in reproductive biology.
Keywords:
ERKGnRH: GPCRJNKMAPK

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