The c-jun kinase/stress-activated pathway: regulation, function and role in human disease

Abstract

c-Jun N-terminal kinases (JNKs), also referred to as stress-activated kinases (SAPKs), were initially characterized by their activation in response to cell stress such as UV irradiation. JNK/SAPKs have since been characterized to be involved in proliferation, apoptosis, motility, metabolism and DNA repair. Dysregulated JNK signaling is now believed to contribute to many diseases involving neurodegeneration, chronic inflammation, birth defects, cancer and ischemia/reperfusion injury. In this review, we present our current understanding of JNK regulation and their involvement in homeostasis and dysregulation in human disease.

Figure 1

Dendrogram showing the relationships between the kinase domains of MKKKs and their ability to activate the JNK/SAPK pathway. MKKK regulation of different MAPK pathways is accumulated from literature survey with an emphasis on MKKK knockout data when available.

Figure 2

A) Organization of MKKK-MKK-MAPK interactions controlled by docking sites, docking domains (CD, ED and docking groove), DVD site and N lobe. See text for discussion. B) CD (common docking) domain (bottom) characterized by acidic residues in C-terminus of MAPK. ED site (middle) is far from CD domain in the primary sequence, the ED site and CD domain are in the same groove on the opposite side of catalytic center [25]. Crystal structures of p38 and MKK3b or MEF2A define a role of another docking groove (top) in binding to φXφ motif in docking sites [28]. Shown in red are the experimentally proved critical residues for docking site interaction.

Figure 2

A) Organization of MKKK-MKK-MAPK interactions controlled by docking sites, docking domains (CD, ED and docking groove), DVD site and N lobe. See text for discussion. B) CD (common docking) domain (bottom) characterized by acidic residues in C-terminus of MAPK. ED site (middle) is far from CD domain in the primary sequence, the ED site and CD domain are in the same groove on the opposite side of catalytic center [25]. Crystal structures of p38 and MKK3b or MEF2A define a role of another docking groove (top) in binding to φXφ motif in docking sites [28]. Shown in red are the experimentally proved critical residues for docking site interaction.

Figure 3

Function of JNK/SAPK scaffolds in organizing the MKKK-MKK4/MKK7- JNK signaling module. Known JNK scaffold proteins are listed in the box. See text for discussion.