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

Yuan Huang; Fatima Rangwala; Patricia C Fulkerson; Bo Ling; Erin Reed; Adrienne D Cox; John Kamholz; Nancy Ratner

doi:10.1038/sj.onc.1207075

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

Journal article

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

Yuan Huang, Fatima Rangwala, Patricia C Fulkerson, Bo Ling, Erin Reed, Adrienne D Cox, John Kamholz and Nancy Ratner

Oncogene, Vol.23(2), pp.368-378

01/15/2004

DOI: 10.1038/sj.onc.1207075

PMCID: PMC2854497

PMID: 14724565

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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.

R-Ras

TC21

Schwann cell

neurofibromin

Ras

chemotaxis

Details

Title: Subtitle: Role of TC21/R-Ras2 in enhanced migration of neurofibromin-deficient Schwann cells
Creators: Yuan Huang - Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267-0521, USA
Fatima Rangwala - Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267-0521, USA
Patricia C Fulkerson - Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267-0521, USA
Bo Ling - Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267-0521, USA
Erin Reed - Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267-0521, USA
Adrienne D Cox - Departments of Radiation Oncology and Pharmacology, CB7512, Lineberger Cancer Center, UNC-CH, Chapel Hill, NC 27599, USA
John Kamholz - Department of Neurology, Wayne State University, Elliman Building 3206, 421 East Canfield, Detroit, MI 48201, USA
Nancy Ratner - Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267-0521, USA
Resource Type: Journal article
Publication Details: Oncogene, Vol.23(2), pp.368-378
DOI: 10.1038/sj.onc.1207075
PMID: 14724565
PMCID: PMC2854497
ISSN: 0950-9232
eISSN: 1476-5594
Language: English
Date published: 01/15/2004
Academic Unit: Neurology; Psychiatry
Record Identifier: 9984020644002771

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