The neurotrophin-3 receptor TrkC directly phosphorylates and activates the nucleotide exchange factor Dbs to enhance Schwann cell migration

被引:55
作者
Yamauchi, J
Chan, JR
Miyamoto, Y
Tsujimoto, G
Shooter, EM
机构
[1] Stanford Univ, Sch Med, Dept Neurobiol, Stanford, CA 94305 USA
[2] Nara Inst Sci & Technol, Dept Cell Biol, Nara 6300101, Japan
[3] Kyoto Univ, Dept Genom Drug Discovery Sci, Kyoto 6068501, Japan
关键词
tyrosine phosphorylation; Rho GTPase; cell motility;
D O I
10.1073/pnas.0501160102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:5198 / 5203
页数:6
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