c-Jun N-terminal kinase 1 (JNK1) is a protein belonging to the mitogen-activated protein kinase (MAPK) family. As a kinase, JNK1 adds phosphate groups to other proteins, altering their activity. It participates in various cellular signaling pathways, helping cells respond to environmental cues and stresses. JNK1 regulates important cellular functions by activating or inhibiting other molecules.
JNK1’s Role in Healthy Cells
JNK1 performs various functions in maintaining healthy cell operation. It is involved in processes such as cell growth and differentiation, guiding cells to mature into specialized types. JNK1 also contributes to programmed cell death, known as apoptosis, a natural process that removes damaged or unneeded cells to maintain tissue health.
This protein also helps cells respond to various forms of stress, including oxidative stress, which occurs when there’s an imbalance between free radicals and antioxidants, and inflammatory signals. JNK1 is activated by specific enzymes, MKK4 and MKK7, which phosphorylate it at particular sites. This activation allows JNK1 to modify the activity of numerous proteins, both within the cell’s nucleus and at its mitochondria.
JNK1 is sometimes referred to as a “stress-activated protein kinase” (SAPK) due to its responsiveness to various environmental challenges, such as UV radiation, infections, and heat shock. The effects of JNK pathway activation can depend on its context and duration, with transient activation sometimes promoting cell survival.
JNK1 and Disease Development
While JNK1 has beneficial roles, its dysregulation, meaning overactivity or underactivity, contributes to the progression of various diseases. For example, JNK1 is implicated in metabolic disorders like type 2 diabetes and obesity. Chronic inflammation, often linked to high-calorie intake, can lead to insulin resistance, a condition where cells don’t respond well to insulin. In these cases, JNK can block insulin signaling pathways.
In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, JNK1 also plays a part. Its aberrant activity can contribute to neuronal damage and cognitive decline. These conditions, like metabolic disorders, often involve chronic inflammation and insulin resistance.
JNK1 is also linked to inflammatory conditions. Its overactivation can promote atherosclerosis, a disease where plaque builds up inside arteries. Studies show that reducing JNK2, another JNK family member, can lessen atherosclerosis progression, suggesting JNK’s role in inflammatory responses within blood vessels.
In certain cancers, JNK1’s involvement is complex and can be contradictory. While JNKs are often associated with promoting programmed cell death, which suppresses tumors, emerging evidence suggests JNK1 can also contribute to the malignant transformation and growth of cancer cells. For instance, JNK1 activation has been shown to be involved in cell transformation and proliferation in response to oncogenic signals, and its genetic disruption in mice has been shown to decrease susceptibility to certain lymphomas.
Therapeutic Targeting of JNK1
Given JNK1’s involvement in various diseases, researchers are exploring strategies to target it therapeutically. The rationale for developing JNK1 inhibitors or modulators is to block or control its harmful activities in disease states. For instance, in cancers where JNK1 promotes tumor growth, inhibitors aim to impede this process.
However, targeting JNK1 is challenging due to its diverse functions in healthy cells. Broad inhibition of JNK1 could disrupt its beneficial roles in cell growth, differentiation, and stress responses, leading to unwanted side effects. This necessitates developing highly specific inhibitors that can selectively target JNK1’s pathological activities without affecting its normal functions.
Several JNK inhibitors have been developed and assessed in preclinical studies, showing promise in various disease models, including certain cancers. For example, some compounds have demonstrated the ability to block tumor growth or reduce the potential of cancer stem cells. However, many of these inhibitors have primarily been studied in the context of fibrotic or inflammatory diseases, with fewer in oncology settings.
One JNK inhibitor, D-JNKI1 (also known as AM-111 or brimapitide), has progressed to Phase II/III clinical trials for acute hearing loss, where local administration might help mitigate systemic side effects. The development of JNK-targeting therapies requires a precise approach, considering the specific JNK protein involved and the exact signaling pathways driving the disease. Further clinical studies are needed to determine the most effective JNK inhibitors for specific conditions and to understand their mechanisms in various physiological processes.