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Vol. 296, Issue 2, 426-433, February 2001

The Thromboxane A2 Receptor Activates Mitogen-Activated Protein Kinase via Protein Kinase C-Dependent Gi Coupling and Src-Dependent Phosphorylation of the Epidermal Growth Factor Receptor

Yunling Gao, Shaoqing Tang, Sharon Zhou and J. Anthony Ware

Department of Medicine, Cardiovascular Division (Y.G., S.T., S.Z., J.A.W.) and Molecular Pharmacology (J.A.W.), Albert Einstein College of Medicine of Yeshiva University, Bronx, New York

The mitogen-activated protein kinase signaling cascade is used by many G protein-coupled receptors to initiate functional events. In this study, activation of the Gq/G11-coupled thromboxane A2 (TxA2) receptor (TP) by the TxA2 mimetic IBOP in ECV304 cells was found to induce extracellular regulated kinase (ERK) phosphorylation and tyrosine phosphorylation of the epidermal growth factor receptor (EGFR), which were inhibited by the TP antagonist SQ29548, the EGFR kinase inhibitor AG1478, the Src family kinase inhibitor PP1, the Gi/o protein inhibitor pertussis toxin (PTX), or the protein kinase C (PKC) inhibitor calphostin C. TP activation also increased Src kinase activity, which was blocked by PTX, PP1, and calphostin C, but not by AG1478, indicating that Src activation occurs before phosphorylation of EGFR. Blockade of Src activity by expression of dominant negative mutant of Src inhibits mitogen-activated protein kinase (MAPK) activation induced by TxA2. ERK activation induced by the PKC activator phorbol myristate acetate was inhibited by PTX, PP1, AG1478, and calphostin C. In contrast, activation of ERK by lysophosphatidic acid, a Gi-coupled receptor activator, was inhibited by PTX, PP1, and AG1478, but not by calphostin C. Thus, TP-stimulated ERK activation requires Gi, which in turn requires PKC activation. Immunoprecipitation of Galpha i showed increased association of Galpha i with TPalpha following PKC activation. In conclusion, TPalpha is directly coupled to the Gi protein by a PKC-regulated mechanism; Gi coupling causes Src-dependent transactivation of the EGFR, which is the dominant pathway in TP-mediated ERK activation.

0022-3565/01/2962-0426$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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