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Betagamma subunits of G(i/o) suppress EGF-induced ERK5 phosphorylation, whereas ERK1/2 phosphorylation is enhanced

Yutaro Obara1, Yumiko Okano, Sachiko Ono

  • 1Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan. obaray@mail.pharm.tohoku.ac.jp

Cellular Signalling
|April 15, 2008
PubMed

Insights

This study reveals that G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases interact to regulate extracellular signal-regulated kinases (ERK5) and (ERK1/2) pathways. Specifically, G(i/o) signaling negatively impacts ERK5 phosphorylation, while positively influencing ERK1/2.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Signal transduction

Background:

  • Extracellular signal-regulated kinases (ERKs) are crucial for cell proliferation, differentiation, and gene expression.
  • ERK5 possesses a unique carboxy-terminal half distinct from ERK1/2.
  • Understanding cross-talk between G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases is vital for deciphering complex cellular responses.

Purpose of the Study:

  • To investigate the cross-talk mechanisms between GPCRs and receptor tyrosine kinases.
  • To elucidate the distinct regulatory roles of G(i/o) signaling on ERK1/2 and ERK5 pathways.
  • To determine the specific molecular mediators involved in the cross-talk, particularly Gbetagamma subunits.

Main Methods:

  • Utilized rat pheochromocytoma (PC12) cells for experiments.
  • Employed pertussis toxin (PTX) to inhibit G(i/o) signaling.
  • Investigated the effects of lysophosphatidic acid (LPA) and epidermal growth factor (EGF) on ERK phosphorylation.
  • Assessed the impact of overexpressing GRK2 and Gbeta/gamma subunits on signaling pathways.

Main Results:

  • Pertussis toxin (PTX) enhanced EGF-induced ERK5 phosphorylation, indicating a negative regulatory role of G(i/o).
  • Lysophosphatidic acid (LPA) attenuated EGF-induced ERK5 phosphorylation via LPA(1) receptor and G(i/o) signaling.
  • LPA activated ERK1/2 independently and potentiated EGF-induced ERK1/2 phosphorylation, suggesting positive regulation by G(i/o).
  • Gbetagamma subunits were identified as key mediators, interacting with the EGF receptor and suppressing ERK5 phosphorylation.

Conclusions:

  • G(i/o) signaling negatively regulates ERK5 phosphorylation while positively regulating ERK1/2.
  • LPA-mediated inhibition of EGF-induced ERK5 phosphorylation occurs through Gbetagamma subunits.
  • This study highlights a novel cross-talk mechanism between GPCRs and receptor tyrosine kinases impacting ERK signaling.

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