Differential Activation of ERK and JNK Mitogen-Activated Protein Kinases by Raf-1 and MEKK

TLDR

Growth factors trigger MAPK signaling, with well‑characterized ERK activation pathways but a less understood JNK pathway, both involving Ras‑mediated activation of Raf‑1 and MEKK. The study shows that EGF/NGF‑induced JNK activation requires H‑Ras, whereas TNF‑α‑induced JNK is Ras‑independent, Raf‑1 drives ERK activation but not JNK, and MEKK activates JNK and only induces ERK upon overexpression, revealing two separate Ras‑dependent MAPK cascades.

Abstract

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 α (TNF-α) 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.