Netrin signal transduction and the guanine nucleotide exchange factor DOCK180 in attractive signaling
Netrin signal transduction and the guanine nucleotide exchange factor DOCK180 in attractive signaling
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DOI：
10.1038/nn2022
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发表时间：
2008-01-01
影响因子：
25
通讯作者：
Rao, Yi
中科院分区：
文献类型：
--
作者：
Li, Xiaoling;Gao, Xue;Rao, Yi
Netrins是典型的轴突导向线索，其吸引人的信号需要小的GTTRIN Rac 1。目前还不清楚Rac 1在netrin通路中是如何调节的。DOCK 180是Rho GTP酶鸟嘌呤核苷酸交换因子新家族的成员。在这里，我们提供的证据表明，DOCK 180在netrin信号转导。Netrin促进蛋白质-蛋白质相互作用复合物的形成，该复合物包括DOCK 180和在结直肠癌（DCC）中缺失的Netrin受体。DOCK 180的抑制减少了Netrin对Rac 1的激活。在脊椎动物神经元中，DOCK 180敲低后，netrin诱导的轴突生长和轴突吸引都受到抑制。DOCK 180的体内功能作用通过其对神经管中连合轴突的投射的需求来证明。这些发现表明，netrin刺激通过DCC招募DOCK 180，然后激活小GTP酶，这表明DOCK 180在介导神经元对netrin-1的吸引反应中起着重要作用。
Netrins are prototypical axon guidance cues whose attractive signaling requires the small GTPase Rac1. It remains unclear how Rac1 is regulated in the netrin pathway. DOCK180 is a member of a new family of guanine nucleotide exchange factors for Rho GTPases. Here we provide evidence implicating DOCK180 in netrin signal transduction. Netrin promoted the formation of a protein-protein interaction complex that included DOCK180 and the netrin receptor deleted in colorectal carcinoma (DCC). Inhibition of DOCK180 reduced activation of Rac1 by netrin. Both axon outgrowth and axon attraction induced by netrin were inhibited after DOCK180 knockdown in vertebrate neurons. The in vivo functional role of DOCK180 was demonstrated by its requirement for projection of commissural axons in the neural tube. These findings indicate that netrin stimulation recruits DOCK180 through DCC, which then activates small GTPases, suggesting an essential role for DOCK180 in mediating attractive responses by neurons to netrin-1.