Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance.
Phosphorylation of DCC by Fyn mediates Netrin-1 signaling in growth cone guidance.
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DOI：
10.1083/jcb.200405053
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发表时间：
2004-11-22
期刊：
影响因子：
--
通讯作者：
Lamarche-Vane N
中科院分区：
文献类型：
--
作者：
Meriane M;Tcherkezian J;Webber CA;Danek EI;Triki I;McFarlane S;Bloch-Gallego E;Lamarche-Vane N
Netrin-1作为一种化学吸引分子，通过与结直肠癌(DCC)中缺失的受体相互作用，引导连合神经元(CN)朝向底板。Netrin-1-DCC信号转导的分子机制尚不清楚。在这里，我们证明了DCC在体内被酪氨酸残基磷酸化，以响应CN的Netrin-1刺激，并且Src家族激酶抑制剂PP2和SU6656阻断了Netrin-1依赖的DCC的磷酸化和轴突生长。PP2还阻断了非洲爪哇视网膜神经节细胞对Netrin-1的反应而发生的重定向，这表明Src激酶在Netrin-1依赖的定向中发挥了重要作用。Fyn，而不是Src，能够在体外磷酸化DCC的胞内区，我们证明了Y1418对于DCC轴突的生长功能是至关重要的。在FYN−/−CN和脊髓外植体中，DCC磷酸化和Netrin-1诱导的轴突生长都受到损害。我们认为DCC受酪氨酸磷酸化的调节，Fyn对轴突对Netrin-1的反应是必不可少的。
Netrin-1 acts as a chemoattractant molecule to guide commissural neurons (CN) toward the floor plate by interacting with the receptor deleted in colorectal cancer (DCC). The molecular mechanisms underlying Netrin-1–DCC signaling are still poorly characterized. Here, we show that DCC is phosphorylated in vivo on tyrosine residues in response to Netrin-1 stimulation of CN and that the Src family kinase inhibitors PP2 and SU6656 block both Netrin-1–dependent phosphorylation of DCC and axon outgrowth. PP2 also blocks the reorientation of Xenopus laevis retinal ganglion cells that occurs in response to Netrin-1, which suggests an essential role of the Src kinases in Netrin-1–dependent orientation. Fyn, but not Src, is able to phosphorylate the intracellular domain of DCC in vitro, and we demonstrate that Y1418 is crucial for DCC axon outgrowth function. Both DCC phosphorylation and Netrin-1–induced axon outgrowth are impaired in Fyn−/− CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1.
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