JNK/SAPK is a member of the MAPK family which was originally identified as a stress-activated kinase linked to the death response (1). More recently, JNK/SAPK has been shown to have additional cellular functions and play a key role in cell growth, differentiation and survival.
JNK/SAPK is a central component in the JNK/SAPK signaling pathway and a variety of environment stresses, inflammatory cytokines, growth factors and GPCR agonists can activate this target and the pathway (2). A variety of environmental stimuli impact the small GTPases of the Rho family (Rac, Rho and cdc42) in the cell membrane which in turn lead to the activation of membrane proximal protein components such as MEKKs, ASK1, TAK1/AB1 or MLK3. These protein kinases then phosphorylate and activate MKK4/7, which mediates the activation of the JNK/SAPK family members (3). There are three isoforms of JNK/SAPK family; these include: JNK1, JNK2, and JNK3. Activated JNK/SAPK can translocate to the nucleus where it can regulate the activity of multiple transcription factors including c-Jun, ATF-2, SMAD4, p53 and Elk1.
JNK/SAPK dysregulation, as a result of oxidative stress, plays an important role in the increased phosphorylation of cytoskeletal proteins found in Alzheimer's disease (AD) (4). In hippocampal and cortical regions of individuals with severe AD, activated phospho-JNK/SAPK become localized exclusively in association with neurofibrillar alterations including neurofibrillary tangles, senile plaque neurites, neuropil threads and granulovacuolar degeneration structures (GVD), completely overlapping with tau-positive neurofibrillary pathology.
Therefore, targeting the JNK/SAPK signaling pathway may offer an effective therapy for pathological conditions of the CNS (5). Recent genetic evidence and emerging pharmacological data indicate that activated JNK could also be critical in causing diabetes, insulin resistance and obesity (6).
1. Basu, S. et al: Stress signals for apoptosis: Ceramide and c-Jun kinase. Oncogene. 1998 Dec 24;17(25):3277-85.
2. Nishina, H. et al: Physiological roles of SAPK/JNK signaling pathway. J Biochem (Tokyo). 2004 Aug;136(2):123-6.
3. Wada, T. et al: Stress kinase MKK7: Savior of cell cycle arrest and cellular senescence. Cell Cycle. 2004 May;3(5):577-9.
4. Zhu, X. et al: Activation and redistribution of c-Jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease. J Neurochem. 2001 Jan;76(2):435-41.
5. Zhang, G. Y. et al : Agents targeting c-Jun N-terminal kinase pathway as potential neuroprotectants. Expert Opin Investig Drugs. 2005 Nov;14(11):1373-83.
6. Bennett, B. L. et al: JNK: A new therapeutic target for diabetes. Curr Opin Pharmacol. 2003 Aug;3(4):420-5.