Review
The c-Jun N-terminal protein kinase family of mitogen-activated protein kinases (JNK MAPKs)

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Abstract

The c-Jun N-terminal protein kinase mitogen-activated protein kinases (JNK MAPKs) are an evolutionarily-conserved family of serine/threonine protein kinases. First identified in 1990 when intraperitoneal injection of the protein synthesis inhibitor cycloheximide activated a 54 kDa protein kinase, the JNK MAPKs have now taken on a prominent role in signal transduction. This research has revealed a number of levels of complexity. Alternative gene splicing is now recognised to result in ten different JNK MAPK isoforms of 46–55 kDa, and these isoforms differ in their substrate affinities. Furthermore, although originally classified as stress-activated protein kinases (SAPKs), or SAPKs, the JNK MAPKs are also critical mediators of signal transduction in response to stimulation by cytokines and some growth factors. JNK MAPKs have been shown to be critical mediators in dorsal closure in developing Drosophila embryos, and targeted knockout of murine JNK MAPKs has suggested a critical involvement of these kinases in mammalian embryonic development. Recent work has also highlighted their importance in programmed cell death. Thus, the JNK MAPKs may provide a critical target for regulation in both normal and diseased states.

Section snippets

An introduction to the mitogen-activated protein kinases (MAPKs)

External stimuli play a major role in regulating complex intracellular processes such as gene expression, cell survival, growth, differentiation or death. Examples of these stimuli include cell–cell and cell–extracellular matrix adhesion and mechanical forces, in addition to the exposure to soluble factors such as growth factors, hormones and cytokines. The mitogen-activated protein kinases (MAPKs) comprise a group of intracellular signal transduction enzymes that allow a cell to respond to

The structure of JNK MAPKs

JNK MAPKs, as typified by JNK1α1 in Fig. 1A, are serine/threonine protein kinases containing all 11 protein kinase subdomains [9]. These motifs comprise the conserved features of protein kinases, namely binding of ATP and peptide substrates, and maintain the conserved protein kinase three-dimensional fold. The structure of JNK3 [10], is shown in Fig. 1B (MMDBId, 10549; PDB Id, 1JNK). As expected for all protein kinases, the small N-terminal lobe (predominantly anti-parallel β-sheets; subdomains

Extracellular activators of the JNK MAPK pathways

Following the exposure of cells to external factors, JNK MAPK activation has been routinely measured by protein kinase activity towards the transcription factor substrate, c-Jun. Thus, mammalian JNK MAPKs have been shown to be activated in response to various extracellular stimuli including growth factors, cytokines and cellular stresses such as heat shock, hyper-osmolarity, UV-radiation and ischemia/reperfusion [6], [11], [15], [16], [17]. Although cytokines and growth factors act via specific

The biological functions of JNK MAPKs

The possible biological functions of the JNK MAPK signal transduction pathway in vivo remain a subject of intense current research. When the studies to evaluate JNK MAPK function are considered, they fall into two categories. A traditional biochemical approach to understanding JNK MAPK function has focused on the identification of the JNK MAPK-specific substrates. As described in Section 4.1, these substrates are predominantly transcription factors, thus suggesting that the effects of JNK MAPKs

Medical applications

Given the diverse roles of JNK MAPKs (e.g. as regulators of the activation and differentiation of T cells in the immune system as reviewed in [95], or as mediators of neuronal apoptosis as reviewed in [65]), there is a great deal of interest in developing specific inhibitors of these kinases. Currently, there are no specific chemical inhibitors of JNK MAPKs available commercially. A number of compounds have been shown to prevent JNK MAPK activation, however, many have other chemical features

Acknowledgements

Work on JNK MAPKs in MAB's laboratory has been supported by the National Heart Foundation, the National Health and Medical Research Council, and the Cancer Foundation of Western Australia. R.K. Barr is a recipient of a Hackett at UWA Postgraduate Student Scholarship.

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