Role of TC21/R-Ras2 in enhanced migration of neurofibromin-deficient Schwann cells.
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.
Huang
Yuan
Y
Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati, College of Medicine, 3125 Eden Ave., Cincinnati, OH 45267-0521, USA.
Rangwala
Fatima
F
Fulkerson
Patricia C
PC
Ling
Bo
B
Reed
Erin
E
Cox
Adrienne D
AD
Kamholz
John
J
Ratner
Nancy
N
D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D002478:Cells, Cultured; D017353:Gene Deletion; D016514:Genes, Neurofibromatosis 1 / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins; D025542:Neurofibromin 1 / Q000172:deficiency* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012583:Schwann Cells / Q000166:cytology* / Q000378:metabolism*; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism
D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D020559:Monomeric GTP-Binding Proteins; D025542:Neurofibromin 1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020663:ras Guanine Nucleotide Exchange Factors; D018631:ras Proteins; C490200:Rras2 protein, mouse