Conditional Inhibition of the Mitogen-activated Protein Kinase Cascade by Wortmannin
DEPENDENCE ON SIGNAL STRENGTH*
- From the ‡Department of Medicine, Division of Signal Transduction, Beth Israel Hospital and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 and the§Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02114
Abstract
Phosphoinositide (PI) 3-kinase and the mitogen-activated protein (MAP) kinase cascades are activated by many of the same ligands. Several groups have reported involvement of PI 3-kinase in the activation of Erk1 and Erk2, whereas many other groups have shown that activation of Erk1 and Erk2 is not sensitive to inhibitors of PI 3-kinase such as wortmannin. Here we show that wortmannin inhibition of the MAP kinase pathway is cell type- and ligand-specific. Wortmannin blocks platelet-derived growth factor (PDGF)-dependent activation of Raf-1 and the MAP kinase cascade in Chinese hamster ovary cells, which have few PDGF receptors, but has no significant effect on Erk activation in Swiss 3T3 cells, which have high levels of PDGF receptors. However, wortmannin blocks activation of Erk proteins if Swiss 3T3 cells are stimulated with lower, physiological levels of PDGF. These results suggest that PI 3-kinase is in an efficient pathway for activation of MAP kinase, but that MAP kinase can be stimulated by a redundant pathway when a large number of receptors are activated. We present evidence that a protein kinase C family member downstream of phospholipase Cγ is involved in the redundant pathway.
Footnotes
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↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵¶ To whom correspondence should be addressed: Harvard Institutes of Medicine, 10th Floor, Division of Signal Transduction, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-0942; Fax: 617-667-0957; E-mail:bduckwor{at}bidmc.harvard.edu.
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↵1 The abbreviations used are: PI, phosphoinositide; PtdIns, phosphatidylinositol; MAP, mitogen-activated protein; PKC, protein kinase C; PDGF, platelet-derived growth factor; CHO, Chinese hamster ovary; PLC, phospholipase C.
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↵2 Y. S. Bae, L. G. Cantley, C.-S. Chen, S.-R. Kim, K.-S. Swon, and S. G. Rhee, submitted for publication.
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↵3 B. C. Duckworth and L. C. Cantley, unpublished data.
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- Received April 16, 1997.
- Revision received August 27, 1997.
