c-Jun N-terminal kinases (JNKs) are also referred to as stress-activated kinases (SAPKs). JNK/SAPKs are involved in proliferation, apoptosis, motility, metabolism and DNA repair. Dysregulation can contribute to many diseases related to neurodegeneration, chronic inflammation, birth defects, cancer, ischemia/reperfusion injury, as well as, obesity and insulin-resistant diabetes. There are three JNK genes (JNK1, JNK2, JNK3). JNK1 and JNK2 are ubiquitously expressed while JNK3 is restricted to brain, heart and testes. The TXY motif in the activation loop of each JNK is dually phosphorylated by specific MAPK kinases (MKKs).
The inhibition of JNKs in metabolic regulation may offer a therapeutic benefit for obesity-induced insulin resistance. The insulin receptor phosphorylates tyrosine residues on insulin receptor substrate 1 (IRS1). The phosphorylated IRS1 functions as a complex scaffolding protein which recruits numerous signaling proteins in the control of insulin signaling and metabolic regulation. JNKs are activated by high fat diet and obesity, in part due to the elevated levels of TNFα and IL-1. The activated JNKs phosphorylate IRS1 at S307 and this results in reduced insulin receptor catalyzed phosphorylation of IRS1. However, studies have suggested that the reduced phosphorylation of S307 correlates with improved insulin sensitivity. Consequently, JNK1 may be an important target in the treatment of obesity and type II diabetes. This is consistent with findings that a cell permeable JNK inhibitory peptide was able to maintain insulin sensitivity in the obese mouse model.