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The thromboxane A2 receptor activates mitogen-activated protein kinase via protein kinase C-dependent Gi coupling and

Y Gao1, S Tang, S Zhou

  • 1Department of Medicine, Cardiovascular Division, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.

The Journal of Pharmacology and Experimental Therapeutics
|February 13, 2001
PubMed

Insights

Thromboxane A2 receptor activation triggers extracellular regulated kinase (ERK) signaling through a G protein pathway. This involves protein kinase C, Src kinase, and epidermal growth factor receptor transactivation.

Area of Science:

  • Cellular signaling pathways
  • G protein-coupled receptors
  • Signal transduction

Background:

  • Mitogen-activated protein kinase (MAPK) cascades are crucial for cellular responses.
  • G protein-coupled receptors (GPCRs) initiate diverse functional events via signaling cascades.
  • The thromboxane A2 (TxA2) receptor (TP) is a GPCR implicated in various physiological processes.

Purpose of the Study:

  • To elucidate the signaling mechanisms by which the TxA2 receptor (TP) activates the MAPK cascade.
  • To investigate the roles of G proteins, Src kinase, epidermal growth factor receptor (EGFR), and protein kinase C (PKC) in TP-mediated signaling.

Main Methods:

  • Activation of ECV304 cells with IBOP (TxA2 mimetic).
  • Inhibition studies using specific antagonists and inhibitors (SQ29548, AG1478, PP1, pertussis toxin, calphostin C).
  • Assessment of extracellular regulated kinase (ERK) and EGFR phosphorylation, Src kinase activity, and G protein involvement via immunoprecipitation.

Main Results:

  • TP activation induced ERK and EGFR phosphorylation, dependent on Gi/o proteins, Src kinase, and PKC.
  • Src kinase activation preceded EGFR phosphorylation and was upstream of MAPK activation.
  • TP signaling to ERK required Gi protein coupling, mediated by PKC, leading to Src-dependent EGFR transactivation.

Conclusions:

  • The TP receptor is directly coupled to Gi proteins via a PKC-regulated mechanism.
  • Gi protein coupling initiates a Src-dependent transactivation of the EGFR.
  • This EGFR transactivation represents the dominant pathway for TP-mediated ERK activation.

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