KSR stimulates Raf-1 activity in a kinase-independent manner

^*Molecular Basis of Carcinogenesis Laboratory, Advanced BioScience Laboratories–Basic Research Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21702; ^†Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720; and ^‡Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007

Contributed by Gerald M. Rubin

Abstract

Kinase suppressor of Ras (KSR) is an evolutionarily conserved component of Ras-dependent signaling pathways. Here, we find that murine KSR (mKSR1) translocates from the cytoplasm to the plasma membrane in the presence of activated Ras. At the membrane, mKSR1 modulates Ras signaling by enhancing Raf-1 activity in a kinase-independent manner. The activation of Raf-1 is mediated by the mKSR1 cysteine-rich CA3 domain and involves a detergent labile cofactor that is not ceramide. These findings reveal another point of regulation for Ras-mediated signal transduction and further define a noncatalytic role for mKSR1 in the multistep process of Raf-1 activation.

Footnotes

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ABBREVIATIONS:

KSR,

kinase suppressor of Ras;

PKC,

protein kinase C;

WT,

wild type;

GVBD,

germinal vesicle breakdown;

MEK,

mitogen and extracellular regulated kinase