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Volume 272, Number 17, Issue of April 25, 1997 pp. 11557-11565
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Reversion of Ras- and Phosphatidylcholine-hydrolyzing Phospholipase C-mediated Transformation of NIH 3T3 Cells by a Dominant Interfering Mutant of Protein Kinase C  Is Accompanied by the Loss of Constitutive Nuclear Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Activity

(Received for publication, July 8, 1996, and in revised form, February 3, 1997)

From the Department of Biochemistry, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway

The transformed phenotype of v-Ras- or Bacillus cereus phosphatidylcholine-hydrolyzing phospholipase C (PC-PLC)-expressing NIH 3T3 cells is reverted by expressing a kinase-defective mutant of protein kinase C  (PKC). We report here that extracellular signal-regulated kinase (ERK)-1 and -2 are constitutively activated in v-Ras- and PC-PLC-transformed cells in the absence of added growth factors. Interestingly, the activated ERKs were exclusively localized to the cell nucleus. Consistently, the transactivating potential of the C-terminal domain of Elk-1, which is activated upon ERK-mediated phosphorylation, was strongly induced in serum-starved cells expressing v-Ras or PC-PLC. Reversion of v-Ras- or PC-PLC-induced transformation by expression of dominant negative PKC abolished the nuclear ERK activation suggesting PKC as a novel, direct or indirect, activator of mitogen-activated protein kinase/ERK kinase in response to activated Ras or elevated levels of phosphatidylcholine-derived diacylglycerol. Transient transfection experiments confirmed that PKC acts downstream of Ras but upstream of mitogen-activated protein kinase/ERK kinase. We found both the v-Ras- and PC-PLC-transformed cells to be insensitive to stimulation with platelet-derived growth factor (PDGF). No detectable receptor level, autophosphorylation, or superinduction of DNA synthesis could be observed in response to treatment with PDGF. Reversion of the transformed cell lines by expression of dominant negative PKC restored the receptor level and the ability to respond to PDGF in terms of receptor autophosphorylation, ERK activation, and induction of DNA synthesis.

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