JNK

Overview

JNK, or c-Jun N-terminal kinase, is a member of the mitogen-activated protein kinase (MAPK) family that is involved in regulating various cellular processes, including cell proliferation, apoptosis, and inflammation. JNK is activated in response to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock.

Structure

JNKs are serine/threonine kinases that are encoded by three genes: JNK1, JNK2, and JNK3. These genes give rise to ten different isoforms through alternative splicing. JNK1 and JNK2 are ubiquitously expressed, whereas JNK3 is primarily found in the brain, heart, and testis.

Activation and Signaling Pathway

JNK is activated through a phosphorylation cascade. The pathway begins with the activation of MAP kinase kinase kinases (MAP3Ks), which phosphorylate and activate MAP kinase kinases (MAP2Ks), specifically MKK4 and MKK7. These kinases then phosphorylate JNK on threonine and tyrosine residues within the activation loop, leading to its activation.

Once activated, JNK translocates to the nucleus where it phosphorylates transcription factors such as c-Jun, ATF2, and Elk-1. This phosphorylation leads to changes in gene expression that mediate the cellular response to stress.

Biological Functions

JNK plays a critical role in:

• Apoptosis: JNK is involved in the regulation of apoptosis, particularly in response to stress signals. It can promote apoptosis by activating pro-apoptotic genes and inhibiting anti-apoptotic pathways.
• Cell Proliferation: JNK influences cell cycle progression and can either promote or inhibit cell proliferation depending on the context.
• Inflammation: JNK is involved in the inflammatory response by regulating the expression of cytokines and other inflammatory mediators.

Clinical Significance

Dysregulation of JNK signaling has been implicated in various diseases, including:

• Cancer: JNK can have both tumor-promoting and tumor-suppressing roles, depending on the type of cancer and the cellular context.
• Neurodegenerative Diseases: JNK is involved in the pathogenesis of diseases such as Alzheimer's disease and Parkinson's disease, where it contributes to neuronal death.
• Diabetes: JNK is implicated in insulin resistance and the development of type 2 diabetes.

Therapeutic Targeting

Given its role in various diseases, JNK is a potential target for therapeutic intervention. Inhibitors of JNK are being explored for their potential to treat inflammatory diseases, cancer, and neurodegenerative disorders.

Also see

• MAPK/ERK pathway
• p38 MAPK
• Apoptosis
• Signal transduction