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Originally published In Press as doi:10.1074/jbc.M001702200 on July 18, 2000

J. Biol. Chem., Vol. 275, Issue 39, 30740-30745, September 29, 2000
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Single Cell Ras-GTP Analysis Reveals Altered Ras Activity in a Subpopulation of Neurofibroma Schwann Cells but Not Fibroblasts*

Larry S. ShermanDagger §, Radhika AtitDagger , Thorsten Rosenbaum, Adrienne D. Cox||**, and Nancy RatnerDagger Dagger Dagger

From the Dagger  Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521, the  Department of Neuropediatrics, Children's Hospital, Heinrich-Heine-University, Dusseldorf, Germany, and the || Departments of Radiation Oncology and Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599-7512

Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by multiple neurofibromas, peripheral nerve tumors containing mainly Schwann cells and fibroblasts. The NF1 gene encodes neurofibromin, a tumor suppressor postulated to function in part as a Ras GTPase-activating protein. The roles of different cell types and of elevated Ras-GTP in neurofibroma formation are unclear. To determine which neurofibroma cell type has altered Ras-GTP regulation, we developed an immunocytochemical assay for active, GTP-bound Ras. In NIH 3T3 cells, the assay detected overexpressed, constitutively activated K-, N-, and Ha-Ras and insulin-induced endogenous Ras-GTP. In dissociated neurofibroma cells from NF1 patients, Ras-GTP was elevated in Schwann cells but not fibroblasts. Twelve to 62% of tumor Schwann cells showed elevated Ras-GTP, unexpectedly revealing neurofibroma Schwann cell heterogeneity. Increased basal Ras-GTP did not correlate with increased cell proliferation. Normal human Schwann cells, however, did not demonstrate elevated basal Ras activity. Furthermore, compared with cells from wild type littermates, Ras-GTP was elevated in all mouse Nf1-/- Schwann cells but never in Nf1-/- mouse fibroblasts. Our results indicate that Ras activity is detectably increased in only some neurofibroma Schwann cells and suggest that neurofibromin is not an essential regulator of Ras activity in fibroblasts.

* This work was supported by National Institutes of Health (NIH) Grant NS28840 (to N. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by NIH Grant NS10297.

** Supported by NIH Grants CA76092 and CA61951.

Dagger Dagger To whom correspondence should be addressed: Dept. of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267-0521. Tel.: 513-558-6079; Fax: 513-558-4454; E-mail: Nancy.Ratner@uc.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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