Context-specific inhibition of JNKs: overcoming the dilemma of protection and damage

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The c-Jun N-terminal kinases (JNKs), which are essential regulators of physiological and pathological processes, are involved in several diseases including diabetes, atherosclerosis, stroke, and Parkinson's and Alzheimer's diseases. Inhibition of JNKs suppresses pathological features of these diseases but the many physiological functions of these enzymes argue against the use of sustained, systemic, nonspecific inhibition in the treatment of these diseases. For example, deletion of the gene that encodes JNK1 prevents insulin resistance but disrupts neuronal cytoarchitecture and initiates the pathology of Alzheimer's disease. Thus, it is not sufficient to inhibit selectively either JNKs or individual isoforms of JNK. Instead, the aim is to inhibit the damaging actions of JNK. This can be achieved using peptides that selectively block molecular domains of individual JNK signaling complexes (exclusively) that form under pathological conditions. To date, peptide inhibitors of JNK have been successful in protecting against ischemia-induced brain damage and insulin resistance following obesity. In this review, we discuss novel pharmacological strategies to inhibit JNK and the limitations of these strategies.

Section snippets

The dichotomy of JNK functions

The vision of personalized medicine is based on the fact that knowing the genetic constitution of a patient will increase treatment efficacy by enabling the medication regimen to be adapted to the person's individual disease subtype. For this purpose, novel small molecules and biological drugs are designed to target single proteins in the signaling network of the cell rather than interfere with global regulators. However, there is one obstacle to this approach: almost all signaling targets in

The context-specific assembly and function of JNK signalosomes

The complexity of JNK signaling originates from several factors: the different activities of the JNK isoforms; the multitude of activating kinases; the different scaffold molecules that provide a basis for the specific interactions between JNKs and their activators; and the variety of compartment-defined substrate proteins (Figure 2).

In recent years, gene-disruption and functional-interference studies have provided evidence for different context-specific tasks for JNKs, which are encoded by

The roles of JNKs in physiological and pathological conditions

What is the clinical risk of inhibiting JNK? In this section, we review briefly some general aspects of the pathological effects of JNKs and their physiological functions to assess the side-effects that are associated with attenuating JNK activity.

Therapeutic specificity: inhibition of isoforms versus signalosomes

As described earlier, therapeutic strategies to combat JNK-dependent diseases require specificity for JNKs (e.g. versus p38 MAPK and extracellular signal-regulated kinases) and for a given JNK (e.g. JNK1 versus either JNK2 or JNK3), and that antagonism of pathological actions does not affect the physiological functions. In this respect, inhibition of c-Jun is not possible because its important role in cellular physiology and adaptive responses to stress cannot be impaired without severe

Concluding remarks

JNKs are clinically relevant mediators of inflammatory diseases such as rheumatoid arthritis and Crohn's disease, acute ischemic damage following myocardial infarction and stroke, insulin resistance that underlies type 2 diabetes, and chronic neurodegeneration in, for example, Alzheimer's disease and Parkinson's disease. Thus, JNKs are interesting and promising targets. However, because of their relevance to cell biology in general, it is not sufficient to block specifically either all JNKs or

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