Ohmichi M, Pang L, Ribon V, Gazit A, Levitzki A, Saltiel A R
Department of Physiology, University of Michigan School of Medicine, Ann Arbor 48109.
Biochemistry. 1993 May 4;32(17):4650-8. doi: 10.1021/bi00068a024.
A series of the synthetic protein kinase inhibitors known as tyrphostins were examined for their effects on the tyrosine autophosphorylation of the pp140c-trk, nerve growth factor (NGF) receptor. One of the tyrphostins, AG879, inhibited NGF-dependent pp140c-trk tyrosine phosphorylation, but did not affect tyrosine phosphorylation of epidermal growth factor or platelet-derived growth factor receptors. In addition, the tyrosine phosphorylation of the receptor-associated protein pp38 was also attenuated by the tyrphostin. This effect was time- and dose-dependent, although inhibition of pp38 phosphorylation occurred earlier and at lower concentrations of the compound. AG879 also inhibited NGF-induced PLC-gamma 1 phosphorylation, phosphatidylinositol-3 (PI3) kinase activation, the association of the tyrosine-phosphorylated proteins pp100 and pp110 with the p85 subunit of PI-3 kinase, mitogen activated protein and raf-1 kinases, and c-fos induction. In addition, AG879 inhibited NGF-induced neurite outgrowth in PC12 cells. These data indicate that tyrosine kinase activity of the pp140c-trk NGF receptor is essential for the cellular actions of this growth factor.
研究了一系列被称为 tyrphostins 的合成蛋白激酶抑制剂对 pp140c-trk（神经生长因子（NGF）受体）酪氨酸自磷酸化的影响。其中一种 tyrphostin，AG879，可抑制 NGF 依赖的 pp140c-trk 酪氨酸磷酸化，但不影响表皮生长因子或血小板衍生生长因子受体的酪氨酸磷酸化。此外，受体相关蛋白 pp38 的酪氨酸磷酸化也被 tyrphostin 减弱。这种作用具有时间和剂量依赖性，尽管对 pp38 磷酸化的抑制在较低浓度的化合物下更早发生。AG879 还抑制 NGF 诱导的 PLC-γ1 磷酸化、磷脂酰肌醇-3（PI3）激酶激活、酪氨酸磷酸化蛋白 pp100 和 pp110 与 PI-3激酶 p85 亚基的结合、丝裂原活化蛋白和 raf-1 激酶以及 c-fos 诱导。此外，AG879 抑制 NGF 诱导的 PC12 细胞神经突生长。这些数据表明，pp140c-trk NGF 受体的酪氨酸激酶活性对于该生长因子的细胞作用至关重要。
