Received for publication June 3, 2004.
Revised September 10, 2004.
Accepted for publication September 16, 2004.

The Protein Kinase C Inhibitor, Go6976, Potentiates Agonist-induced MAP Kinase Activation through Tyrosine phosphorylation of the Epidermal Growth Factor Receptor

Abstract

Protein kinase C isoforms are important transducers of signals from G protein-coupled receptors (GPCRs) to diverse cellular targets, including extracellularly signal regulated kinases 1 and 2 (ERK1/2). Clone 9 rat hepatocytes (C9 cells) express receptors for angiotensin II (Ang II) type 1 (AT1-R), lysophosphatidic acid (LPA) and epidermal growth factor (EGF), and their stimulation causes transient ERK1/2 phosphorylation through transactivation of the EGF-R. Inhibition of PKC by Go6983, or PKC depletion by prolonged PMA treatment, attenuated ERK1/2 activation by Ang II and PMA, but not by LPA and EGF. In contrast, another PKC inhibitor, Go6976, enhanced basal and agonist-stimulated phosphorylation of ERK1/2, which was not due to 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), since the PTP inhibitor, sodium orthovanadate, mimicked the effects of Go6976. Selective blockade of EGF-R kinase by AG1478 abolished the ERK1/2 activation induced by Go6976. Similar experiments were conducted in HEK293 cells, which express receptors for LPA and EGF but exhibit no significant cross-communication between them. While 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 CHO 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.

Key words: Angiotensin, NGF/EGF, Gq/11 family, Protein tyr Phosphatases, Phosphorylation/Dephosphorylation, MAP Kinase

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