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K-ras Is Critical for Modulating Multiple c-kit-Mediated Cellular Functions in Wild-Type and Nf1^+/– Mast Cells¹

Waleed F. Khalaf^*,, Feng-Chun Yang^,, Shi Chen^,, Hilary White^,, Waylan Bessler^,, David A. Ingram^, and D. Wade Clapp^2,*,,

^* Department Microbiology & Immunology, Department of Pediatrics, and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202

p21^ras (Ras) proteins and GTPase-activating proteins (GAPs) tightly modulate extracellular growth factor signals and control multiple cellular functions. The specific function of each Ras isoform (H, N, and K) in regulating distinct effector pathways, and the role of each GAP in negatively modulating the activity of each Ras isoform in myeloid cells and, particularly, mast cells is incompletely understood. In this study, we use murine models of K-ras- and Nf1-deficient mice to examine the role of K-ras in modulating mast cell functions and to identify the role of neurofibromin as a GAP for K-ras in this lineage. We find that K-ras is required for c-kit-mediated mast cell proliferation, survival, migration, and degranulation in vitro and in vivo. Furthermore, the hyperactivation of these cellular functions in Nf1^+/– mast cells is decreased in a K-ras gene dose-dependent fashion in cells containing mutations in both loci. These findings identify K-ras as a key effector in multiple mast cell functions and identify neurofibromin as a GAP for K-ras in mast cells.

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 study was supported by the National Institutes of Health (NCI R01 CA 74177) and the American Heart Association (0410094Z).

² Address correspondence and reprint requests to Dr. D. Wade Clapp, Indiana University School of Medicine, Cancer Research Institute, 1044 West Walnut Street, R4 402, Indianapolis, IN 46202. E-mail address: dclapp{at}iupui.edu

³ Abbreviations used in this paper: GAP, GTPase-activating protein; NF1, neurofibromatosis type 1; GRD, GAP-related domain of NF1; WT, wild type; Kit-l, Kit ligand.

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