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Role of TC21/R-Ras2 in enhanced migration of neurofibromin-deficient Schwann cells

Oncogene volume 23, pages 368–378 (2004)Cite this article

Abstract

The neurofibromatosis type 1 tumor suppressor protein neurofibromin, is a GTPase activating protein for H-, N-, K-, R-Ras and TC21/R-Ras2 proteins. We demonstrate that Schwann cells derived from Nf1-null mice have enhanced chemokinetic and chemotactic migration in comparison to wild-type controls. Surprisingly, this migratory phenotype is not inhibited by a farnesyltransferase inhibitor or dominant-negative (dn) (N17)H-Ras (which inhibits H-, N-, and K-Ras activation). We postulated that increased activity of R-Ras and/or TC21/R-Ras2, due to loss of Nf1, contributes to increased migration. Mouse Schwann cells (MSCs) express R-Ras and TC21/R-Ras2 and their specific guanine exchange factors, C3G and AND-34. Infection of Nf1-null MSCs with a dn(43N)R-Ras adenovirus (to inhibit both R-Ras and TC21/R-Ras2 activation) decreases migration by approximately 50%. Conversely, expression of activated (72L)TC21/R-Ras2, but not activated (38V)R-Ras, increases migration, suggesting a role of TC21/R-Ras2 activation in the migration of neurofibromin-deficient Schwann cells. TC21/R-Ras2 preferentially couples to the phosphatidylinositol 3-kinase (PI3-kinase) and MAP kinase pathways. Treatment with a PI3-kinase or MAP kinase inhibitor reduces Nf1-null Schwann cell migration, implicating these TC21 effectors in Schwann cell migration. These data reveal a key role for neurofibromin regulation of TC21/R-Ras2 in Schwann cells, a cell type critical to NF1 tumor pathogenesis.

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Acknowledgements

We thank the Ratner lab for helpful discussion and advice. We thank Merck Research Laboratories for the FTI. This work was supported by NIH-NS28840 to NR. FR was supported by the Medical Scientist Training Program's John H Wulsin Fellowship.

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  1. Contributed equally

Authors and Affiliations

  1. Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, College of Medicine, 3125 Eden Ave., Cincinnati, 45267-0521, OH, USA

    Yuan Huang, Fatima Rangwala, Patricia C Fulkerson, Bo Ling, Erin Reed & Nancy Ratner

  2. Departments of Radiation Oncology and Pharmacology, CB7512, Lineberger Cancer Center, UNC-CH, Chapel Hill, 27599, NC, USA

    Adrienne D Cox

  3. Department of Neurology, Wayne State University, Elliman Building 3206, 421 East Canfield, Detroit, 48201, MI, USA

    John Kamholz

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Correspondence to Nancy Ratner.

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Huang, Y., Rangwala, F., Fulkerson, P. et al. Role of TC21/R-Ras2 in enhanced migration of neurofibromin-deficient Schwann cells. Oncogene 23, 368–378 (2004). https://doi.org/10.1038/sj.onc.1207075

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