“A sneak-peek into understanding the functional specificity of the c-Jun-amino-terminal kinases”.

Kanaga Sabapathy, National Cancer Center, Singapore

The c-Jun-amino terminal kinases (JNKs), which include JNK1, 2 and 3, are pleotrophic kinases required for both apoptosis and proliferation, and are deregulated in various diseases such as cancer and neurological pathologies. While expression of JNK3 is restricted to the brain and heart tissues, JNK1 and JNK2 are ubiquitously expressed, and are combinedly required for survival through embryogenesis. Interestingly, both overlapping and specific functions have been attributed to the JNK proteins, based on over a decade of analyses of the individual JNK knockout mice. Importantly, these data have opened up possibilities for targeting the JNK proteins for therapeutic intervention. While general JNK-inhibitors have been generated, the fundamental problem in fully harnessing the potential provided by the JNK pathway has been due to the lack of specificity to target the specific JNK proteins involved in the pathological contexts. In an attempt to address this issue, we hypothesized that there would exist selective JNK-interacting partners that will either regulate the various JNK functions specifically, or be selectively regulated by various JNKs. To explore this possibility, we have performed a limited JNK1 and JNK2-interactome analysis, and have identified various partners. Interestingly, many of the partners belonged primarily to 2 groups: those that were bound to JNK1 alone, or those that were bound to both JNK1 and JNK2. However, the number of candidates that were able to bind to JNK2 alone was very limited. The analysis also revealed the potential involvement of the JNK proteins in several important physiological processes such as DNA-repair and many metabolic pathways, besides the well known cell death and proliferation processes. Data will be presented to highlight the specificity of the JNK proteins, using a few selected examples