The JNK signal transduction pathway
Introduction
The response of a cell to changes in its environment is induced, in part, by a diverse array of intracellular signaling pathways. These pathways serve to relay, amplify and integrate signals from extracellular stimuli, ultimately resulting in a genomic and physiological response. In mammalian systems, these responses include cellular proliferation, differentiation, development, the inflammatory response and apoptosis. Mitogen-activated protein (MAP) kinases are one such family of signaling proteins.
The c-Jun NH2-terminal kinase (JNK) pathway represents one sub-group of MAP kinases that is activated primarily by cytokines and exposure to environmental stress [1, 2]. Specific stimuli trigger the activation of MAP3Ks, which then phosphorylate and activate the MAP2K isoforms MKK4 and MKK7, which in turn phosphorylate and activate JNK [1, 2]. Components of the JNK pathway can be organized into signaling complexes, mediated by one of the protein kinases (e.g. a MAP3K or a MAP2K) or by a scaffold protein, for example a member of the JNK-interacting protein (JIP) family [3]. A major target of the JNK signaling pathway is the activator protein-1 (AP-1) transcription factor, which is activated, in part, by the phosphorylation of c-Jun and related molecules [1, 2]. This review aims to highlight recent progress in JNK-related research; we refer the reader to earlier reviews [1, 2, 3] for references and discussion of previous work.
Section snippets
Novel components of the JNK signaling pathway
Recent research has provided new insights into regulatory components of the JNK signaling pathway. These fall broadly into three categories: upstream regulators (e.g. MAP3Ks); down-stream inhibitors (e.g. phosphatases); and scaffold proteins (e.g. JIPs).
The canonical JNK signaling cascade has been well characterized; however, the specific role of MAP3K in the response to various stimuli remains largely unresolved. Recent studies of the MAP3K isoform transforming growth factor-β activated kinase
JNK in cell death
A role for JNK in apoptosis is well established [1, 2]; however, the mechanism by which this occurs is controversial and appears to be stimulus- and tissue-specific [35]. One explanation for some of the differences observed could be the temporal aspect of JNK activation, and two recent studies have addressed this issue [36]. First, Chang and colleagues have described how sustained, but not transient, JNK activation promotes TNF-α killing via the E3 ubiquitin ligase Itch-mediated degradation of
Mechanism of JNK-induced activation of the mitochondrial apoptotic pathway
Primary fibroblasts prepared from Jnk1−/−Jnk2−/− embryos and from Mkk4−/−Mkk7−/− embryos exhibit marked defects in stress-induced apoptosis [46, 47]. Detailed analysis demonstrated that the apoptosis defect was associated with failure to release mitochondrial pro-apoptotic proteins, including cytochrome c. Indeed, micro-injection experiments demonstrated that the mutant cells did not exhibit defects in apoptosis if cytochrome c was directly injected into the cytoplasm [47]. These studies
JNK in cancer
JNK is implicated in oncogenic transformation; however, its role in tumor development remains controversial [66]. A role for the JNK pathway in tumorigenesis is supported by the high levels of JNK activity found in several cancer cell lines [66]. Indeed, in a recent study using a Drosophila model of tumor formation, oncogenic Raf and JNK were shown to cooperate to induce massive hyperplasia [67]. Studies of JNK signaling in mammals also support a role for JNK in tumor development. Thus, Nateri
JNK in diabetes and metabolism
Biochemical studies have established that JNK phosphorylates the insulin receptor substrate-1 (IRS-1) at the inhibitory site Ser-307 [77, 78]. JNK activation can therefore suppress signal transduction by the insulin receptor. These observations implicate the JNK signaling pathway in insulin resistance, metabolic syndrome and type 2 diabetes. Indeed, JNK is activated in obese mice [79], in part because of lipotoxic stress [80] that may be mediated by a mechanism involving the ataxia
JNK in lifespan
Aging of a eukaryotic organism is affected by its nutritional state and by its ability to repair oxidative damage. Consequently, signal transduction systems that control metabolism and oxidative stress responses influence lifespan. Two recent studies have shown that JNK can control lifespan in Drosophila and C. elegans by promoting phosphorylation of the forkhead protein FOXO [63•, 89•]. Oh and colleagues show that JNK promotes daf-16 (FOXO) activity, which regulates life span and stress
Conclusions
Significant progress towards understanding the function of the JNK signaling pathway has been achieved during the past few years. The determination of atomic structures for components of the JNK signaling pathway and also some complexes formed by these components represents a critical step towards a more complete understanding. Recent studies using the chemical genetic approach [90] to define the function of JNK in vivo using mice with a germ-line point mutation that confers sensitivity to a
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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