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Molecular Pharmacology

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Research ArticleArticle

The Protein Kinase C Inhibitor Go6976 [12-(2-Cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole] Potentiates Agonist-Induced Mitogen-Activated Protein Kinase Activation through Tyrosine Phosphorylation of the Epidermal Growth Factor Receptor

Bukhtiar H. Shah, J. Alberto Olivares-Reyes and Kevin J. Catt
Molecular Pharmacology January 2005, 67 (1) 184-194; DOI: https://doi.org/10.1124/mol.104.003533
Bukhtiar H. Shah
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J. Alberto Olivares-Reyes
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Kevin J. Catt
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Abstract

Protein kinase C (PKC) isoforms are important transducers of signals from G protein-coupled receptors (GPCRs) to diverse cellular targets, including extracellular signal-regulated kinases 1 and 2 (ERK1/2). Clone 9 rat hepatocytes (C9 cells) express receptors for angiotensin II (Ang II) type 1, lysophosphatidic acid (LPA), and epidermal growth factor (EGF), and their stimulation causes transient ERK1/2 phosphorylation through transactivation of the epidermal growth factor receptor (EGF-R). Inhibition of PKC by Go6983 [2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl)maleimide], or PKC depletion by prolonged phorbol 12-myristate 13-acetate (PMA) treatment, attenuated ERK1/2 activation by Ang II and PMA, but not by LPA and EGF. In contrast, another PKC inhibitor, Go6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole], enhanced basal and agonist-stimulated phosphorylation of ERK1/2, which was not caused by alteration in receptor binding and internalization, stimulation of inositol phosphate production, or activation of Pyk2 and Src tyrosine kinases. However, Go6976 enhanced agonist-induced tyrosine phosphorylation of the EGF receptor, possibly through inhibition of protein tyrosine phosphatase (PTP), because the PTP inhibitor sodium orthovanadate mimicked the effects of Go6976. Selective blockade of EGF-R kinase by AG1478 [4-(3-chloroanilino)6,7-dimethoxyquinazoline] abolished the ERK1/2 activation induced by Go6976. Similar experiments were conducted in human embryonic kidney 293 cells, which express receptors for LPA and EGF but exhibit no significant cross-communication between them. Although Go6976 caused a significant increase in EGF-induced tyrosine phosphorylation of the EGF-R and subsequent ERK1/2 activation, it had no such effects on LPA-induced responses. In Chinese hamster ovary cells, which express receptors for LPA but not for EGF, Go6976 also had no significant effect on LPA-induced ERK1/2 activation. These data indicate that Go6976 potentiates agonist-induced ERK1/2 activation through stimulation of tyrosine phosphorylation of the EGF-R.

  • Received June 3, 2004.
  • Accepted September 16, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (1)
Molecular Pharmacology
Vol. 67, Issue 1
1 Jan 2005
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Research ArticleArticle

The Protein Kinase C Inhibitor Go6976 [12-(2-Cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole] Potentiates Agonist-Induced Mitogen-Activated Protein Kinase Activation through Tyrosine Phosphorylation of the Epidermal Growth Factor Receptor

Bukhtiar H. Shah, J. Alberto Olivares-Reyes and Kevin J. Catt
Molecular Pharmacology January 1, 2005, 67 (1) 184-194; DOI: https://doi.org/10.1124/mol.104.003533

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Research ArticleArticle

The Protein Kinase C Inhibitor Go6976 [12-(2-Cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole] Potentiates Agonist-Induced Mitogen-Activated Protein Kinase Activation through Tyrosine Phosphorylation of the Epidermal Growth Factor Receptor

Bukhtiar H. Shah, J. Alberto Olivares-Reyes and Kevin J. Catt
Molecular Pharmacology January 1, 2005, 67 (1) 184-194; DOI: https://doi.org/10.1124/mol.104.003533
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