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The MAPK Scaffold Kinase Suppressor of Ras Is Involved in ERK Activation by Stress and Proinflammatory Cytokines and Induction of Arthritis¹

Angela M. Fusello^*, Laura Mandik-Nayak^*, Fei Shih, Robert E. Lewis, Paul M. Allen^* and Andrey S. Shaw^2,*

^* Department of Pathology and Department of Immunology, and Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110; and Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198

The MAPK ERK is required for LPS-induced TNF production by macrophages. Although the scaffold kinase suppressor of Ras (KSR)1 is required for efficient Erk activation by mitogenic stimuli, the role of KSR1 in ERK activation by inflammatory and stress stimuli is unknown. In this study, we examined the effects of KSR deficiency on ERK activation by stress stimuli and show that ERK activation by TNF, IL-1, and sorbitol is attenuated in the absence of KSR1. To determine the significance of this defect in vivo, we tested KSR-deficient mice using a passive transfer model of arthritis. We found that the induction of arthritis is impaired in the absence of KSR. Thus, KSR plays a role in ERK activation during inflammatory and stress responses both in vitro and in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Cancer Institute and the Pfizer/Washington University Biomedical Research Agreement (to A.S.S.).

² Address correspondence and reprint requests to Dr. Andrey S. Shaw, Department of Pathology, Washington University School of Medicine, 660 South Euclid, Box 8118, St. Louis, MO 63110. E-mail address: shaw{at}pathbox.wustl.edu

³ Abbreviation used in this paper: KSR, kinase suppressor of Ras; MEF, mouse embryonic fibroblast.