The c-Fes protein-tyrosine kinase accelerates NGF-induced differentiation of PC12 cells through a PI3K-dependent mechanism.
The c-Fes protein-tyrosine kinase accelerates NGF-induced differentiation of PC12 cells through a PI3K-dependent mechanism.
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DOI：
10.1016/s0898-6568(02)00089-x
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发表时间：
2003-03
影响因子：
4.8
通讯作者：
A. Shibata;C. E. Laurent;T. Smithgall
中科院分区：
文献类型：
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作者：
A. Shibata;C. E. Laurent;T. Smithgall
c-fes原癌基因编码一种非受体蛋白酪氨酸激酶（Fes），参与骨髓造血细胞的分化。Fes还在几种神经元细胞类型和血管内皮中表达，提示在发育中具有更广泛的功能。为了研究Fes在神经元分化中的作用，我们研究了神经生长因子（NGF）刺激后Fes表达对PC 12细胞突起生长的影响。表达Fes野生型和激活突变体的PC 12细胞比对照细胞延长过程更快，长度更长。相反，激酶失活的Fes的表达没有影响，表明与NGF的合作需要Fes激酶活性。用NGF短期处理PC 12-Fes细胞增强了Fes的酪氨酸磷酸化，表明NGF受体的上游调节。Fes介导的神经突生长的加速被wortmannin和LY 294002阻断，暗示Fes诱导的反应中的磷脂酰肌醇3-激酶（PI 3 K）激活。相比之下，MEK抑制剂PD 98059没有效果，表明Ras-Erk通路不参与。这些数据提供了第一个证据，Fes可能有助于神经元细胞的形态分化，通过增强神经生长因子信号通过PI 3 K途径。
The c-fes protooncogene encodes a non-receptor protein-tyrosine kinase (Fes) that has been implicated in the differentiation of myeloid haematopoietic cells. Fes is also expressed in several neuronal cell types and the vascular endothelium, suggestive of a more general function in development. To examine the role of Fes in neuronal differentiation, we investigated the effect of Fes expression on process outgrowth in PC12 cells following stimulation with nerve growth factor (NGF). PC12 cells expressing wild-type and activated mutants of Fes extended processes faster and of greater length than control cells. In contrast, expression of kinase-inactive Fes was without effect, indicating that cooperation with NGF requires Fes kinase activity. Short-term treatment of PC12-Fes cells with NGF enhanced tyrosine phosphorylation of Fes, suggesting upstream regulation by the NGF receptor. Fes-mediated acceleration of neurite outgrowth was blocked by wortmannin and LY294002, implicating phosphatidylinositol 3-kinase (PI3K) activation in the Fes-induced response. In contrast, the MEK inhibitor PD98059 was without effect, suggesting that the Ras–Erk pathway is not involved. These data provide the first evidence that Fes may contribute to morphological differentiation of neuronal cells by enhancing NGF signalling through the PI3K pathway.