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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

Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

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 for publication June 3, 2004.

Accepted for publication September 16, 2004.

Address correspondence to: Dr. Buktiar H. Shah, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, Bldg. 49, Rm. 6A36, National Institutes of Health, Bethesda, MD 20892-4510. E-mail: shahb{at}mail.nih.gov

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