High resolution

Module 2: Figure JNK signalling

The organization and topology of the c-Jun N-terminal kinase (JNK) pathway.

The c-Jun N-terminal kinase (JNK) pathway can be activated in many ways, including via different receptor mechanisms and by various environmental stresses such as osmotic, redox and radiation stress. These different inputs are transduced by separate mechanisms that all feed into the JNK signalling cascade. With regard to receptor activation, the JNK pathway can be activated by various cytokines such as interleukin-1 as illustrated here. The interleukin-1 receptor (IL-1R) is composed of two receptor-binding domains that interact with interleukin-1 and a non-binding accessory protein. Once activated by interleukin-1, the IL-1R recruits the adaptor protein tumour-necrosis-factor-receptor-associated factor 6 (TRAF6), which then recruits the mitogen-activated protein kinase kinase kinase (MAPKKK) called transforming growth factor β-activated kinase 1 (TAK1) responsible for initiating the phosphorylation cascade by phosphorylating MAPK/extracellular-signal-regulated kinase (ERK) kinase kinase 1 (MEKK1). The MEKK1 then phosphorylates the dual-specificity protein kinase MAPK kinase 7 (MKK7) responsible for phosphorylating the tyrosine and threonine residues on JNK. This activation cascade occurs in the vicinity of the plasma membrane, where it is organized by the scaffolding protein JNK-interacting protein 1 (JIP1). Once JNK is phosphorylated, it leaves the multimolecular activation complex and then diffuses into the nucleus, where it activates transcription factors responsible for controlling processes such as proliferation, apoptosis and embryonic development.