The neurotrophin-3 receptor TrkC directly phosphorylates and activates the nucleotide exchange factor Dbs to enhance Schwann cell migration
The neurotrophin-3 receptor TrkC directly phosphorylates and activates the nucleotide exchange factor Dbs to enhance Schwann cell migration
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DOI：
10.1073/pnas.0501160102
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发表时间：
2005-04-05
影响因子：
11.1
通讯作者：
Shooter, EM
中科院分区：
文献类型：
--
作者：
Yamauchi, J;Chan, JR;Shooter, EM
在周围神经系统的发育过程中，雪旺细胞（形成髓磷脂的神经胶质细胞）在开始髓鞘形成之前沿着轴突迁移。我们之前证明，内源性神经营养素 3 (NT3) 通过 TrkC 酪氨酸激酶受体发挥作用，增强髓鞘形成前雪旺细胞的迁移。该信号通路由 c-Jun N 末端激酶 (JNK) 级联介导，并受 Rho GTPases Rac1 和 Cdc42 调节。然而，TrkC 和 GTPases 之间的联系却缺失。在这里，我们展示了鸟嘌呤核苷酸交换因子 (GEF)，Dbl 的姐姐 (Dbs)，与 TrkC 偶联以激活雪旺细胞中的 Cdc42。此外，TrkC 直接磷酸化 Dbs，从而诱导 Cdc42-GEF 活性。总之，TrkC 的激活通过直接酪氨酸磷酸化调节 Dbs 来触发雪旺细胞迁移，从而提供了一种膜受体酪氨酸激酶可以诱导 Rho GTPase-GEF 激活的机制。
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.