DIFFERENTIAL ACTIVATION OF ERK AND JNK MITOGEN-ACTIVATED PROTEIN-KINASES BY RAF-1 AND MEKK

Growth factors activate mitogen-activated protein kinases (MAPKs), inc luding 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 activat ion is more obscure. Activation of JNK by epidermal growth factor (EGF ) or nerve growth factor (NGF) was dependent on H-Ras activation, wher eas JNK activation by tumor necrosis factor alpha (TNF-alpha) was Ras- independent. Ras activates two protein kinases, Raf-1 and MEK (MAPK, o r ERK, kinase) kinase (MEKK). Raf-1 contributes directly to ERK activa tion but not to JNK activation, whereas MEKK participated in JNK activ ation but caused ERK activation only after overexpression. These resul ts demonstrate the existence of two distinct Ras-dependent MAPK cascad es-one initiated by Raf-1 leading to ERK activation, and the other ini tiated by MEKK leading to JNK activation.