The Neurotrophin-3 Receptor TrkC Directly Phosphorylates and Activates the Nucleotide Exchange Factor Dbs to Enhance Schwann Cell Migration

During the development of the peripheral nervous system, Schwann cells, the myelin-forming glia, migrate along axons before initiating myelination. We previously demonstrated that endogenous neurotrophin-3 (NT3) acting through the TrkC tyrosine kinase receptor enhances migration of premyelinating Sc...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-04, Vol.102 (14), p.5198-5203
Main Authors: Yamauchi, Junji, Chan, Jonah R., Miyamoto, Yuki, Tsujimoto, Gozoh, Shooter, Eric M.
Format: Article
Language:English
Subjects:
Animals
Antibodies
Biological Sciences
cdc42 GTP-Binding Protein - metabolism
Cell adhesion & migration
Cell Movement - drug effects
Cell Movement - physiology
Cells
Cells, Cultured
COS Cells
Enzymes
Guanine Nucleotide Exchange Factors - genetics
Guanine Nucleotide Exchange Factors - metabolism
Humans
Inks
JNK Mitogen-Activated Protein Kinases - metabolism
Myelination
Nervous system
Neurotrophin 3 - metabolism
Neurotrophin 3 - pharmacology
Nucleotides
Phosphorylation
Receptor, trkC - metabolism
Receptors
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Schwann cells
Schwann Cells - cytology
Schwann Cells - drug effects
Schwann Cells - metabolism
Signal Transduction
Small interfering RNA
Transfection
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Summary:During the development of the peripheral nervous system, Schwann cells, the myelin-forming glia, migrate along axons before initiating myelination. We previously demonstrated that endogenous neurotrophin-3 (NT3) acting through the TrkC tyrosine kinase receptor enhances migration of premyelinating Schwann cells. This signaling pathway is mediated by the c-Jun N-terminal kinase (JNK) cascade regulated by the Rho GTPases Rac1 and Cdc42. However, missing is the link between TrkC and the GTPases. Here, we show that a guanine-nucleotide exchange factor (GEF), Dbl's big sister (Dbs), couples with TrkC to activate Cdc42 in Schwann cells. Furthermore, TrkC directly phosphorylates Dbs, thereby inducing the Cdc42-GEF activity. Taken together, activation of TrkC triggers Schwann cell migration by regulating Dbs upon direct tyrosine phosphorylation, providing a mechanism whereby a membrane receptor tyrosine kinase can induce the activation of Rho GTPase-GEFs.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0501160102