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Molecular and Cellular Biology, November 1999, p. 7672-7680, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Antagonistic Effects of Protein Kinase C alpha  and delta  on Both Transformation and Phospholipase D Activity Mediated by the Epidermal Growth Factor Receptor

Armand Hornia, Zhimin Lu, Taiko Sukezane, Minghao Zhong, Troy Joseph, Paul Frankel, and David A. Foster*

Department of Biological Sciences, Hunter College of The City University of New York, New York, New York 10021

Received 13 August 1998/Returned for modification 4 November 1998/Accepted 23 June 1999

Downregulation of protein kinase C delta  (PKC delta ) by treatment with the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) transforms cells that overexpress the non-receptor class tyrosine kinase c-Src (Z. Lu et al., Mol. Cell. Biol. 17:3418-3428, 1997). We extended these studies to cells overexpressing a receptor class tyrosine kinase, the epidermal growth factor (EGF) receptor (EGFR cells); like c-Src, the EGF receptor is overexpressed in several human tumors. In contrast with expectations, downregulation of PKC isoforms with TPA did not transform the EGFR cells; however, treatment with EGF did transform these cells. Since TPA downregulates all phorbol ester-responsive PKC isoforms, we examined the effects of PKC delta - and PKC alpha -specific inhibitors and the expression of dominant negative mutants for both PKC delta  and alpha . Consistent with a tumor-suppressing function for PKC delta , the PKC delta -specific inhibitor rottlerin and a dominant negative PKC delta  mutant transformed the EGFR cells in the absence of EGF. In contrast, the PKC alpha -specific inhibitor Go6976 and expression of a dominant negative PKC alpha  mutant blocked the transformed phenotype induced by both EGF and PKC delta  inhibition. Interestingly, both rottlerin and EGF induced substantial increases in phospholipase D (PLD) activity, which is commonly elevated in response to mitogenic stimuli. The elevation of PLD activity in response to inhibiting PKC delta , like transformation, was dependent upon PKC alpha  and restricted to the EGFR cells. These data demonstrate that PKC isoforms alpha  and delta  have antagonistic effects on both transformation and PLD activity and further support a tumor suppressor role for PKC delta  that may be mediated by suppression of tyrosine kinase-dependent increases in PLD activity.

* Corresponding author. Mailing address: Department of Biological Sciences, Hunter College of The City University of New York, 695 Park Ave., New York, NY 10021. Phone: (212) 772-4075. Fax: (212) 772-5227. E-mail: foster{at}genectr.hunter.cuny.edu.

Molecular and Cellular Biology, November 1999, p. 7672-7680, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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