Minden A, Lin A, McMahon M, Lange-Carter C, Dérijard B, Davis R J, Johnson G L, Karin M
Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla 92093-0636.
Science. 1994 Dec 9;266(5191):1719-23. doi: 10.1126/science.7992057.
Growth factors activate mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs) and Jun kinases (JNKs). Although the signaling cascade from growth factor receptors to ERKs is relatively well understood, the pathway leading to JNK activation is more obscure. Activation of JNK by epidermal growth factor (EGF) or nerve growth factor (NGF) was dependent on H-Ras activation, whereas JNK activation by tumor necrosis factor alpha (TNF-alpha) was Ras-independent. Ras activates two protein kinases, Raf-1 and MEK (MAPK, or ERK, kinase) kinase (MEKK). Raf-1 contributes directly to ERK activation but not to JNK activation, whereas MEKK participated in JNK activation but caused ERK activation only after overexpression. These results demonstrate the existence of two distinct Ras-dependent MAPK cascades--one initiated by Raf-1 leading to ERK activation, and the other initiated by MEKK leading to JNK activation.
生长因子可激活丝裂原活化蛋白激酶（MAPK），包括细胞外信号调节激酶（ERK）和Jun激酶（JNK）。尽管从生长因子受体到ERK的信号级联反应已得到较为充分的了解，但导致JNK激活的途径却更为模糊。表皮生长因子（EGF）或神经生长因子（NGF）对JNK的激活依赖于H-Ras的激活，而肿瘤坏死因子α（TNF-α）对JNK的激活则不依赖于Ras。Ras激活两种蛋白激酶，即Raf-1和MEK（MAPK，或ERK，激酶）激酶（MEKK）。Raf-1直接促进ERK的激活，但不促进JNK的激活，而MEKK参与JNK的激活，但只有在过表达后才会导致ERK的激活。这些结果表明存在两种不同的Ras依赖性MAPK级联反应——一种由Raf-1启动，导致ERK激活，另一种由MEKK启动，导致JNK激活。
