Figure 1.

JNK signaling pathway. A number of stimuli activate the JNK signaling cascade including TNF, free fatty acids (FFA) and extra- or intracellular reactive oxygen species (ROS). Upstream events are poorly defined but result in the activation of one or more MAPK kinase kinases (MAPKKK), several of which are indicated. MAPKKKs activate the JNK MAPK kinases (MAPKK), MKK4 and MKK7, which phosphorylate and activate JNK. The level or duration of JNK activation is negatively regulated by phosphatase action, and ROS may stimulate JNK activation through the inhibition of phosphatase activity. Activated JNK1 and JNK2 isoforms phosphorylate the AP-1 subunit c-Jun, increasing its transcriptional activity. As a heterodimer with another subunit such as c-Fos, c-Jun binds to AP-1 promoter regions, increasing gene expression. Alternatively, JNK may also alter protein levels through the phosphorylation and activation of ubiquitin E3 ligase that promotes protein degradation. Black lines indicate stimulatory pathways and red lines indicate inhibitory pathways. ASK1, apoptosis signal-stimulating kinase 1; MLK, mixed-lineage protein kinases; TAK-1, TGF-β-activated kinase 1, TNFR1, TNF receptor 1, TRAF2, TNF receptor associated protein 2.