MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines

Abstract

Mitogen-activated protein kinases (MAPKThe mitogen-activated protein kinases (MAPKs) represent an evolutionarily conserved signaling mechanism that is used by cells to respond to changes in their environment (Schaeffer and Weber 1999). The activation of MAPK is mediated by dual phosphorylation on a ThrXaa-Tyr motif located in the kinase activation loop. This phosphorylation is increased in stimulated cells by members of a group of MAPK kinases. These enzymes have dual substrate specificity and can phosphorylate both Thr and Tyr. Studies of a large number of MAPKs demonstrate that this mechanism of activation is conserved in many organisms, including plants, yeast, nematodes, insects, and mammals.Two different MAPK kinases (MKK4 and MKK7) are implicated in the activation of the c-Jun NH 2 -terminal kinase (JNK) group of MAPK (Davis 2000). The presence of two MAPK kinases in a single MAPK signaling module is striking because genetic analysis indicates only a single MAPK kinase in each of the MAPK signaling modules of yeast (Schaeffer and Weber 1999). However, the organization of the JNK signaling pathway is similar to that of other mammalian MAPK modules. Thus, the ERK group of MAPK is activated by MKK1/MKK2 and the p38 group of MAPK is activated by MKK3/MKK6 (Schaeffer and Weber 1999). The presence of two MAPK kinases is therefore a common feature of the organization of mammalian MAPK signaling modules. The functional significance of the dual MAPK kinases found in mammalian MAPK signaling pathways is unclear.Studies of mice demonstrate that both the Mkk4 (Yang et al. 1997;Ganiatsas et al. 1998;Nishina et al. 1999) and Mkk7 genes (Dong et al. 2000) are required for embryonic viability. This observation indicates that the MKK4 and MKK7 protein kinases serve nonredundant functions in vivo. Genetic analysis of the Mkk4 (Han et al. 1998) and Mkk7 (Glise et al. 1995) genes in Drosophila supports this conclusion. However, the molecular basis for the difference in signaling by MKK4 and MKK7 is unclear. Differences in the expression pattern of MKK4 and MKK7 in tissues may be a contributing factor. Alternatively, the distinct biochemical properties of MKK4 and MKK7 may be critical for the nonredundant functions of these protein kinases in vivo.Comparison of the biochemical properties of MKK4 and MKK7 indicates that these protein kinases have different substrate specificities. Thus, in vitro assays demonstrate that MKK4 can activate both JNK and p38 MAPK (Derijard et al. 1995;Lin et al. 1995). In contrast, MKK7 selectively activates only JNK (Holland et al.

Cellular response to oxidative stress: Signaling for suicide and survival*

“…An important question in the field is how do such a diverse array of stresses initiate these signaling cascades? Recent studies suggest that different signals may rely on different MAPKKK and/or MAPK (Tournier et al, 2001). For oxidant-induced activation of these pathways, changes in the cellular redox state may be a key factor (Adler et al, 1999a).…”

MAPK signaling in inflammation-associated cancer development

“…Upstream kinases MKK4 and MKK7 phosphorylate JNK on tyrosine and threonine (Dong et al, 2000;Lawler et al, 1998;Tournier et al, 2001). Both MKK4 and MKK7 are required for full activation of JNKs, since overexpression of MKK4 could not substitute reduced proliferation of MKK7-null cells and vice versa (Wada et al, 2004).…”

JNK2 mediates TNF-induced cell death in mouse embryonic fibroblasts via regulation of both caspase and cathepsin protease pathways

“…33 UV-light-and MMS-induced apoptosis is also impaired in pMEFs isolated from mice lacking the expression of JNKactivating kinases MKK4 and MKK7. 34 Interestingly, however, Fas-mediated apoptosis in both thymocytes and pMEFs has been reported to be independent of JNK. 31,33 What is the role of JNK in TNFR1-mediated apoptosis?…”