Yaka R, Gamliel A, Gurwitz D, Stein R
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel.
J Cell Biochem. 1998 Sep 1;70(3):425-32. doi: 10.1002/(sici)1097-4644(19980901)70:3<425::aid-jcb15>3.0.co;2-j.
Activation of receptor tyrosine kinases stimulates a diverse array of cellular responses such as proliferation and differentiation. The first events in the signal transduction pathways mediated by different receptor tyrosine kinases are similar and include activation of the mitogen-activated protein kinase (MAPK) pathway and the induction of immediate early genes. The precise signaling pathways leading to each of the cellular responses mediated by receptor tyrosine kinases are still unknown, although it has been proposed that sustained activation of the MAPK pathway by receptor tyrosine kinases such as the nerve growth factor (NGF) receptor TrkA is sufficient to induce differentiation in PC12 cells. In the present study we examined the effect of NGF on mutant PC12 cells that were derived spontaneously in our cultures. NGF induced normal activation of immediate early genes in these cells, whereas the activation of some delayed response genes, as well as neurite outgrowth, was impaired. Furthermore, activation of the NGF-induced extracellular signal-regulated kinase (ERK) in these cells was transient, not sustained. These results support the hypothesis that sustained activation of ERK plays an important role in activating the induction of delayed response genes. However, sustained ERK activation is not a mandatory condition for the promotion of all the features of differentiated PC12 cells, as NGF could induce transcription of the delayed response gene, transin, in PC12 mutant cells. Taken together, our results suggest that NGF induces differentiation of PC12 cells via several signaling pathways, an important one of which is the MAPK pathway.
受体酪氨酸激酶的激活会刺激多种细胞反应，如增殖和分化。由不同受体酪氨酸激酶介导的信号转导途径中的初始事件相似，包括丝裂原活化蛋白激酶（MAPK）途径的激活和即刻早期基因的诱导。尽管有人提出，诸如神经生长因子（NGF）受体TrkA等受体酪氨酸激酶对MAPK途径的持续激活足以诱导PC12细胞分化，但导致受体酪氨酸激酶介导的每种细胞反应的确切信号通路仍不清楚。在本研究中，我们检测了NGF对我们培养物中自发产生的突变PC12细胞的影响。NGF诱导这些细胞中即刻早期基因的正常激活，而一些延迟反应基因的激活以及神经突生长则受损。此外，这些细胞中NGF诱导的细胞外信号调节激酶（ERK）的激活是短暂的，而非持续的。这些结果支持了ERK的持续激活在激活延迟反应基因诱导中起重要作用的假说。然而，持续的ERK激活并非促进分化的PC12细胞所有特征的必要条件，因为NGF可在PC12突变细胞中诱导延迟反应基因转胶酶原激活因子（transin）的转录。综上所述，我们的结果表明，NGF通过多种信号通路诱导PC12细胞分化，其中重要的一条是MAPK途径。
