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 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.
Yamauchi
Junji
J
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Chan
Jonah R
JR
Miyamoto
Yuki
Y
Tsujimoto
Gozoh
G
Shooter
Eric M
EM
D000818:Animals; D019556:COS Cells; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020933:Neurotrophin 3 / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D020812:Receptor, trkC / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; D020933:Neurotrophin 3; D011994:Recombinant Proteins; D020812:Receptor, trkC; D048031:JNK Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein