Activation of EGF receptor kinase by L1-mediated homophilic cell interactions
Activation of EGF receptor kinase by L1-mediated homophilic cell interactions
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DOI：
10.1091/mbc.e03-05-0333
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发表时间：
2004-04-01
影响因子：
3.3
通讯作者：
Hortsch, M
中科院分区：
文献类型：
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作者：
Islam, R;Kristiansen, LV;Hortsch, M
神经细胞黏附分子(CAM)在神经发生和轴突生长以及轴突颤动和寻路过程中起着重要的作用。其中一些发育过程需要激活细胞信号级联反应。药理学和遗传学证据表明，L1型CAM的轴突生长促进活性至少部分是通过神经元受体酪氨酸激酶(RTK)，尤其是成纤维细胞生长因子和表皮生长因子受体的刺激而实现的。长期以来，人们一直怀疑神经钙调蛋白可能与RTK发生物理作用，但尚未直接证实它们被特定的细胞黏附事件激活。在这里，我们报道了果蝇L1型CAM神经胶质细胞的功能获得条件导致了发育中的果蝇翅膀中深刻的感觉轴突寻路缺陷。这种表型可以通过减少果蝇EGF受体基因的正常基因剂量来抑制。此外，在果蝇S2细胞中，由人L1-CAM介导的细胞黏附导致细胞接触部位人EGF酪氨酸激酶的特异性激活，EGF受体与L1-CAM分子发生物理相互作用。因此，在体外和体内，L1型CaM能够促进EGF受体信号的黏附依赖激活。
Neural cell adhesion molecules (CAMs) are important players during neurogenesis and neurite outgrowth as well as axonal fasciculation and pathfinding. Some of these developmental processes entail the activation of cellular signaling cascades. Pharmacological and genetic evidence indicates that the neurite outgrowth-promoting activity of L1-type CAMs is at least in part mediated by the stimulation of neuronal receptor tyrosine kinases (RTKs), especially FGF and EGF receptors. It has long been suspected that neural CAMs might physically interact with RTKs, but their activation by specific cell adhesion events has not been directly demonstrated. Here we report that gain-of-function conditions of the Drosophila L1-type CAM Neuroglian result in profound sensory axon pathfinding defects in the developing Drosophila wing. This phenotype can be suppressed by decreasing the normal gene dosage of the Drosophila EGF receptor gene. Furthermore, in Drosophila S2 cells, cell adhesion mediated by human L1-CAM results in the specific activation of human EGF tyrosine kinase at cell contact sites and EGF receptors engage in a physical interaction with L1-CAM molecules. Thus L1-type CAMs are able to promote the adhesion-dependent activation of EGF receptor signaling in vitro and in vivo.