SAPK/JNK Signaling

c-Jun N-terminal kinases (JNKs), also referred to as stress-activated protein kinases (SAPKs), are characterized by their activation in response to cell stress such as UV irradiation, death ligands, inflammatory cytokines and growth factors. JNK/SAPKs play a central role in cell proliferation, apoptosis, motility, metabolism and DNA repair.As with all Mitogen activated protein kinases (MAPKs), the JNKs are part of a three kinase module. Thus a MAPK kinase (MKK) activates JNK, while a MAPKK kinase (MKKK) activates the MKKs. MKK4 and MKK7 phosphorylate specific threonine and tyrosine residues within the activation loop of JNK resulting in activation. There are at least 20 MKKKs of which around 14 activate the MKK4/MKK7-JNK pathway. The large numbers of MKKKs that activate the JNK pathway underscore the importance of this pathway in cellular responses to diverse external stimuli. Examples of the activating MKKKs include MEKK1/2/3/4, dual leucine zipper-bearing kinase (DLK), Mixed lineage kinase 3(MLK3) and TGFβ activated kinase 1 (TAK1). Many MKKKs are activated by the RAS and RHO family of GTPases and kinases like hematopoietic progenitor kinase 1 (HPK1). Another important aspect of JNK signaling involves scaffolding proteins like the JNK interacting protein (JIP) which is required for JNK activation and the induction of apoptosis.The activation of the JNK/SAPK pathway culminates in the phosphorylation of c-Jun which is a member of the AP-1 transcription factors. In addition to c-Jun, JNK also phosphorylates and activates other transcription factors like Activating transcription factor-2 (ATF2) and p53 while inhibiting nuclear factor of activated T-cells (NFAT). Activation of the SAPK/JNK pathway by stress stimuli thus results in transcriptional regulation of stress related genes.This pathway highlights the important molecular events involved in JNK/SAPK signaling.