C-Jun N-terminal kinases

C-Jun N-terminal kinases (JNK), also known as stress-activated protein kinases (SAPK), are a family of protein kinases involved in various cellular processes, including cell proliferation, apoptosis, and inflammatory response. JNKs are part of the mitogen-activated protein kinase (MAPK) family, which play critical roles in transmitting signals from the cell surface to the nucleus.

Function

JNKs are activated in response to various stress stimuli, such as ultraviolet light, heat shock, cytokines, and osmotic shock. Once activated, JNKs can phosphorylate a range of substrates, including members of the transcription factor AP-1 family, such as c-Jun, ATF-2, and ELK-1. Phosphorylation of these transcription factors leads to changes in gene expression that are associated with cell differentiation, apoptosis, and inflammatory response.

Structure

JNKs are encoded by three different genes in mammals: JNK1, JNK2, and JNK3. Each gene can produce several isoforms through alternative splicing, resulting in a diversity of JNK proteins. Structurally, JNKs consist of a kinase domain, which is responsible for their enzymatic activity, and regulatory domains that control their activation and substrate specificity.

Activation and Regulation

JNK activation is typically mediated through a signaling cascade involving MAPK kinase kinases (MAP3Ks) and MAPK kinases (MKKs), specifically MKK4 and MKK7. These kinases phosphorylate JNK on a threonine and a tyrosine residue in the activation loop, enhancing its kinase activity. The regulation of JNK activity is complex and involves both positive and negative feedback mechanisms, as well as interactions with scaffold proteins that can modulate the specificity and duration of JNK signaling.

Role in Disease

Due to their involvement in cell stress responses, JNKs have been implicated in a variety of diseases. Overactivation of JNK signaling has been associated with neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, where it can contribute to neuronal death. In cancer, JNKs can have both tumor-suppressing and tumor-promoting roles, depending on the context. JNKs are also involved in the development of insulin resistance and type 2 diabetes through their effects on inflammatory responses and apoptosis in insulin-sensitive tissues.

Therapeutic Potential

Given their central role in various diseases, JNKs represent a potential target for therapeutic intervention. Inhibitors of JNK signaling have shown promise in preclinical models of neurodegeneration, cancer, and diabetes. However, the development of JNK inhibitors for clinical use faces challenges, including the need for specificity to avoid off-target effects and the potential for adverse effects due to the broad role of JNKs in normal cellular functions.

See Also

• Mitogen-activated protein kinase
• Apoptosis
• Cell proliferation
• Inflammatory response