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Molecular and Cellular Biology, August 1999, p. 5523-5534, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Kinase Suppressor of Ras Forms a Multiprotein Signaling Complex and Modulates MEK Localization

Scott Stewart,1 Meera Sundaram,2,3 Yanping Zhang,4 Jeeyong Lee,1 Min Han,2 and Kun-Liang Guan1,5,*

Department of Biological Chemistry1 and Institute of Gerontology,5 University of Michigan Medical School, Ann Arbor, Michigan 48109-0606; Howard Hughes Medical Institute, Department of MCD Biology, University of Colorado, Boulder, Boulder, Colorado 803092; Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-61453; and Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina 27599-72954

Genetic screens for modifiers of activated Ras phenotypes have identified a novel protein, kinase suppressor of Ras (KSR), which shares significant sequence homology with Raf family protein kinases. Studies using Drosophila melanogaster and Caenorhabditis elegans predict that KSR positively regulates Ras signaling; however, the function of mammalian KSR is not well understood. We show here that two predicted kinase-dead mutants of KSR retain the ability to complement ksr-1 loss-of-function alleles in C. elegans, suggesting that KSR may have physiological, kinase-independent functions. Furthermore, we observe that murine KSR forms a multimolecular signaling complex in human embryonic kidney 293T cells composed of HSP90, HSP70, HSP68, p50CDC37, MEK1, MEK2, 14-3-3, and several other, unidentified proteins. Treatment of cells with geldanamycin, an inhibitor of HSP90, decreases the half-life of KSR, suggesting that HSPs may serve to stabilize KSR. Both nematode and mammalian KSRs are capable of binding to MEKs, and three-point mutants of KSR, corresponding to C. elegans loss-of-function alleles, are specifically compromised in MEK binding. KSR did not alter MEK activity or activation. However, KSR-MEK binding shifts the apparent molecular mass of MEK from 44 to >700 kDa, and this results in the appearance of MEK in membrane-associated fractions. Together, these results suggest that KSR may act as a scaffolding protein for the Ras-mitogen-activated protein kinase pathway.

* Corresponding author. Mailing address: Department of Biological Chemistry, Institute of Gerontology, University of Michigan Medical School, Ann Arbor, MI 48109-0606. Phone: (734) 763-3030. Fax: (734) 763-4581. E-mail: kunliang{at}umich.edu.

Molecular and Cellular Biology, August 1999, p. 5523-5534, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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