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Molecular and Cellular Biology, May 2002, p. 3035-3045, Vol. 22, No. 9
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.9.3035-3045.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Kinase Suppressor of Ras (KSR) Is a Scaffold Which Facilitates Mitogen-Activated Protein Kinase Activation In Vivo

AnhCo Nguyen,1 W. Richard Burack,1 Jeffrey L. Stock,2 Robert Kortum,3 Oleg V. Chaika,3 Maryam Afkarian,4 William J. Muller,5 Kenneth M. Murphy,4 Deborah K. Morrison,6 Robert E. Lewis,3 John McNeish,2 and Andrey S. Shaw1*

Department of Pathology and Immunology,1 Department of Pathology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110,4 Department of Exploratory Medicinal Sciences, Central Research, Pfizer, Inc., Groton, Connecticut 06340,2 Eppley Institute for Research in Cancer and Allied Diseases, Department of Biochemistry and Molecular Biology, Omaha, Nebraska 68198,3 Institute for Molecular Biology and Biotechnology, Department of Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada,5 Regulation of Cell Growth Laboratory, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 217026

Received 6 December 2001/ Returned for modification 15 January 2002/ Accepted 30 January 2002

While scaffold proteins are thought to be key components of signaling pathways, their exact function is unknown. By preassembling multiple components of signaling cascades, scaffolds are predicted to influence the efficiency and/or specificity of signaling events. Here we analyze a potential scaffold of the Ras/mitogen-activated protein kinase (MAPK) pathway, kinase suppressor of Ras (KSR), by generating KSR-deficient mice. KSR-deficient mice were grossly normal even though ERK kinase activation was attenuated to a degree sufficient to block T-cell activation and inhibit tumor development. Consistent with its role as a scaffold, high-molecular-weight complexes containing KSR, MEK, and ERK were lost in the absence of KSR. This demonstrates that KSR is a bona fide scaffold that is not required for but enhances signaling via the Ras/MAPK signaling pathway.

* Corresponding author. Mailing address: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8118, St. Louis, MO 63110. Phone: (314) 362-6311. Fax: (314) 362-8888. E-mail: shaw{at}immunology.wustl.edu.

Molecular and Cellular Biology, May 2002, p. 3035-3045, Vol. 22, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.9.3035-3045.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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