Abstract
Mitogen kinase kinase 4 (MKK4) and mitogen kinase kinase 7 (MKK7) are members of the MAP2K family that can activate downstream mitogen-activated protein kinases (MAPKs). MKK4 has been implicated in the activation of both c-Jun N-terminal kinase (JNK) and p38 MAPK, while MKK7 has been reported to activate only JNK in response to different stimuli. The stimuli, as well as the cell type determine which MAP2K member will mediate a given response. In various cell types, MKK7 contributes to the activation of downstream MAPKs, JNK, which is known to regulate essential cellular processes, such as cell death, differentiation, stress response, and cytokine secretion. Previous studies have also implicated the role of MKK7 in stress signaling pathways and cytokine production. However, little is known about the degree to which MKK4 and MKK7 contribute to innate immune responses in macrophages or during inflammation in vivo. To address this question and to elucidate the role of MKK4 and MKK7 in macrophage and in vivo, we developed MKK4- and MKK7-deficient mouse models with tamoxifen-inducible Rosa26 CreERT. This study reports that MKK7 is required for JNK activation both in vitro and in vivo. Additionally, we demonstrated that MKK7 in macrophages is necessary for lipopolysaccharide (LPS)-induced cytokine production, M1 polarization, and migration, which appear to be a major contributor to the inflammatory response in vivo. Conversely, MKK4 plays a significant, but minor role in cytokine production in vivo.
Highlights
The mitogen-activated protein kinases (MAPKs) are an evolutionarily conserved signaling mechanism that controls a range of important cellular functions, including differentiation, stress response, and apoptosis [1,2]
Jun N-terminal kinase (JNK) kinases can be activated by different MAP2Ks, which include mitogen kinase kinase 4 (MKK4) and mitogen kinase kinase 7 (MKK7) proteins [2,17]. p38 MAPK can be activated mainly by MKK3 and MKK6, but MKK4 can play a role in some circumstances [9]
We have established the role of mixed lineage kinases (MLKs), a member of mitogen-activated protein kinases kinase kinase (MAP3K) family in
Summary
The mitogen-activated protein kinases (MAPKs) are an evolutionarily conserved signaling mechanism that controls a range of important cellular functions, including differentiation, stress response, and apoptosis [1,2]. The activation of MAPK JNK and p38 are mediated by several members of the evolutionary conserved upstream mitogen-activated protein kinases kinase (MAP2K) family [6,7,8]. Such diversity in the repertoire of upstream activators might, in turn, define the specificity of the stimuli-induced pathway activation. Both mitogen kinase kinase 4 (MKK4) and mitogen kinase kinase 7 (MKK7) are MAP2K family members. The cell type and activation stimuli determine whether MAP2K, MKK7 or MKK4, plays a significant role in the downstream targets of JNK and p38 activation in vitro and in vivo [11,12,13]
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