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- Title
Role of TC21/R-Ras2 in enhanced migration of neurofibromin-deficient Schwann cells.
- Authors
Yuan Huang; Rangwala, Fatima; Fulkerson, Patricia C.; Bo Ling; Reed, Erin; Cox, Adrienne D.; Kamholz, John; Ratner, Nancy
- 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.Oncogene (2004) 23, 368-378. doi:10.1038/sj.onc.1207075
- Subjects
TUMOR suppressor proteins; GUANOSINE triphosphatase; CELLS; ADENOVIRUSES; RAS oncogenes
- Publication
Oncogene, 2004, Vol 23, Issue 2, p368
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1207075