A novel SAPK/JNK kinase, MKK7, stimulated by TNFalpha and cellular stresses

Abstract

Stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), a member of the MAP kinase (MAPK) superfamily, is thought to play a key role in a variety of cellular responses. To date, SEK1/MKK4, one of the MAP kinase kinase (MAPKK) family of molecules, is the only SAPK/JNK kinase that has been cloned. Here we have cloned, identified and characterized a novel member of the mammalian MAPKKs, designated MKK7. MKK7 is most similar to the mediator of morphogenesis, hemipterous (hep), in Drosophila. Immunochemical studies have identified MKK7 as one of the major SAPK/JNK-activating kinases in osmotically shocked cells. While SEK1/ MKK4 can activate both the SAPK/JNK and p38 subgroups of the MAPK superfamily, MKK7 is specific for the SAPK/JNK subgroup. MKK7 is activated strongly by tumour necrosis factor α (TNFα) as well as by environmental stresses, whereas SEK1/MKK4 is not activated by TNFα. Column fractionation studies have shown that MKK7 is a major activator for SAPK/ JNK in the TNFα-stimulated pathway. Moreover, we have found that overexpression of MKK7 enhances transcription from an AP-1-dependent reporter construct. Thus, MKK7 is an evolutionarily conserved MAPKK isoform which is specific for SAPK/JNK, is involved in AP-1-dependent transcription and may be a crucial mediator of TNFα signalling.

PKC δ mediates ionizing radiation-induced activation of c-Jun NH2-terminal kinase through MKK7 in human thyroid cells

“…MKK4 activates both JNK and p38 MAPK (Derijard et al, 1995;Han et al, 1996;Jiang et al, 1996;Lin et al, 1995;Sanchez et al, 1994), while MKK7 selectively activates JNK (Holland et al, 1997;Lu et al, 1997;Moriguchi et al, 1997;Tournier et al, 1997Tournier et al, , 1999. In this study, we clari®ed that MKK7 but not MKK4 was involved in the process of IR-induced and PKC d-dependent JNK activation.…”

“…However, inhibition of IR-induced JNK activation by MKK7KR was partial, suggesting the existence of unknown JNKK in this IR-PKC d-JNK pathway. Moriguchi et al (1997) have indeed indicated the presence of another JNKK at the level of fractionation by column chromatography using lysates of stress-stimulated cells. Other studies have demonstrated that MKK7 is mainly activated by cytokines (e.g.…”

Tumor necrosis factor signaling

“…Thus, phosphorylation of threonine 180 by MKK7 could be sufficient to activate JNK in response to TNF and MKK4 could enhance TNF-MKK7-mediated JNK activation by phosphorylation of tyrosine 182. Remarkably, TNF activates MKK7 but not MKK4, 141 suggesting that the basal activity of MKK4 is sufficient to allow maximal activation of JNK in response to TNF. While knockout mice have clearly proven the pivotal roles of TRAF2 and MKK7 for TNF-R1-mediated JNK activation, the nature and function of the MAP3K, which must fill the gap between TRAF2 and MKK7, has not been satisfactorily identified yet.…”

Proteomic identification of C/EBP-DBD multiprotein complex: JNK1 activates stem cell regulator C/EBPα by inhibiting its ubiquitination

“…Immunoblot against HA after immunoprecipitation of C/EBPa shows that C/EBPa is significantly ubiquitinated when co-transfected with HA-Ubi (Figure 3f; lane 4), whereas this ubiquitination was inhibited in HA-Ubi-, C/EBPa-and MKK7-co-transfected cells where JNK1 is activated by MKK7 (Figure 3f; lane5). MKK7 directly interacts with JNK1 and activates it by receiving signals from upstream kinases (Moriguchi et al, 1997). Next, we demonstrate that inactive JNK indeed leads to enhanced C/EBPa ubiquitination; C/EBPa was co-transfected with varying amount of MKK7 (Figure 3g; lanes 3, 4 and 5) and kinase-dead JNK mutant (HA-JNK*; Figure 3g; lane 6) together with HA-Ubi; 24 h post-transfection, RIPA extract was prepared and separated on 10% SDS-PAGE.…”