Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway
Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway
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DOI：
10.1074/jbc.m007333200
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发表时间：
2001-03-23
影响因子：
4.8
通讯作者：
Vigny, M
中科院分区：
文献类型：
--
作者：
Souttou, B;Brunet-De Carvalho, N;Vigny, M
间变性淋巴瘤激酶（ALK）是一种新型神经元孤儿受体酪氨酸激酶，主要在中枢和外周神经系统的特定区域瞬时表达，表明在其正常发育和功能中发挥作用。为了确定ALK是否可以在神经元分化中发挥作用，我们建立了一个模型系统，使我们能够模拟该受体的正常激活。我们在PC12细胞中表达了一种嵌合蛋白，其中受体的胞外结构域被小鼠IgG 2b Fc结构域取代。Fc结构域诱导嵌合蛋白的二聚化和寡聚化，导致受体磷酸化和活化，从而模拟配体结合的作用，而野生型ALK仍为单体非磷酸化蛋白。嵌合体的表达诱导了PC12细胞的分化，但野生型ALK或嵌合体的激酶失活形式的表达不诱导分化。对参与这一过程的信号通路的分析指出了丝裂原活化蛋白激酶级联的重要作用。这些结果与ALK在神经元分化中的作用一致。
Anaplastic lymphoma kinase (ALK) is a novel neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems, suggesting a role in its normal development and function. To determine whether ALK could play a role in neuronal differentiation, we established a model system that allowed us to mimic the normal activation of this receptor. We expressed, in PC12 cells, a chimeric protein in which the extracellular domain of the receptor was replaced by the mouse IgG 2b Fc domain. The Fc domain induced the dimerization and oligomerization of the chimeric protein leading to receptor phosphorylation and activation, thus mimicking the effect of ligand binding, whereas the wild type ALK remained as a monomeric nonphosphorylated protein. Expression of the chimera, but not that of the wild type ALK or of a kinase inactive form of the chimera, induced the differentiation of PC12 cells. Analysis of the signaling pathways involved in this process pointed to an essential role of the mitogen-activated protein kinase cascade. These results are consistent with a role for ALK in neuronal differentiation.