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Volume 272, Number 7, Issue of February 14, 1997 pp. 3915-3923
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Negative Modulation of Membrane Localization of the Raf-1 Protein Kinase by Hyperphosphorylation

(Received for publication, July 3, 1996, and in revised form, October 3, 1996)

Markus Wartmann Dagger , Paul Hofer Dagger , Patrick Turowski Dagger , Alan R. Saltiel par and Nancy E. Hynes Dagger

From the Dagger  Friedrich Miescher Institute, P. O. Box 2543, CH-4002 Basel, Switzerland, and the par  Department of Signal Transduction, Parke Davis Research Division, Warner Lambert Company, Ann Arbor, Michigan 48105

The serine/threonine-specific protein kinase Raf-1 plays a key role in mitogenic signal transduction by coupling Ras to the mitogen-activated protein (MAP) kinase cascade. Ras-mediated translocation to the plasma membrane represents a crucial step in the process of serum-stimulated Raf-1 kinase activation. The exact role of the multisite phosphorylation in Raf regulation, however, is not clear. We have previously reported that the mobility shift-associated hyperphosphorylation of Raf correlates with a reduction of serum-stimulated Raf kinase activity (Wartmann, M., and Davis, R. J. (1994) J. Biol. Chem. 269, 6695-6701).

Here we show that incubation of serum-starved CHO cells with D609, a purported inhibitor of phosphatidylcholine-specific phospholipase C, also results in a mobility shift of Raf-1 that is due to hyperphosphorylation on sites identical to those observed following mitogen stimulation. Subcellular fractionation analyses revealed that D609-induced mobility shift-associated hyperphosphorylation was paralleled by a decreased membrane association of Raf-1. Similar results were obtained in an in vitro reconstitution system. Furthermore, PD98059, a specific inhibitor of activation of the MAP kinase kinase MEK, prevented D609-induced Raf hyperphosphorylation and restored the amount of membrane-bound Raf to control levels. Taken together, these data suggest that mobility shift-associated hyperphosphorylation of Raf-1, by virtue of reducing the amount of plasma membrane-bound Raf-1, represents a negative feedback mechanism contributing to the desensitization of the MAP kinase signaling cascade.


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