Ras activation of a Rac1 exchange factor, Tiam1, mediates neurotrophin-3-induced Schwann cell migration.
Endogenous neurotrophins positively and negatively regulate migration of premyelinating Schwann cells before the initiation of myelination. Neurotrophin-3 (NT3) acting through the TrkC receptor tyrosine kinase stimulates Schwann cell migration via the Rho GTPases Rac1 and Cdc42. We previously demonstrated that TrkC directly phosphorylates and activates Dbs, the guanine-nucleotide exchange factor (GEF) for Cdc42, to partially mediate Schwann cell migration. Here, we identify T lymphoma invasion and metastasis (Tiam) 1 as the Rac1-specific guanine-nucleotide exchange factor involved in NT3-induced Schwann cell migration. Furthermore, the interaction between the small GTPase Ras and Tiam1 plays an essential role in the activation of Rac1. Taken together, these results suggest that NT3 activation of TrkC stimulates Schwann cell migration through two parallel signaling units, Ras/Tiam1/Rac1 and Dbs/Cdc42, and that Schwann cell migration is uniquely regulated in the case of Ras and Rac1, by two different types of small GTPases.
Yamauchi
Junji
J
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305-5125, USA.
Miyamoto
Yuki
Y
Tanoue
Akito
A
Shooter
Eric M
EM
Chan
Jonah R
JR
D000704:Analysis of Variance; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D009363:Neoplasm Proteins / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000378:metabolism / Q000502:physiology*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D020933:Neurotrophin 3; D034741:RNA, Small Interfering; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513259:Tiam1 protein, rat; D020764:cdc42 GTP-Binding Protein; D018631:ras Proteins