MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration

Xia, Ying; Makris, Constantin; Su, Bing; Li, Erguang; Yang, Jianhua; Nemerow, Glen R.; Karin, Michael

doi:10.1073/pnas.97.10.5243

Cited by 259 publications

(223 citation statements)

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“…IRAK then interacts with the TNF receptor-associated factor (TRAF)6 [24] and references therein], and oligomerisation of TRAF6 and TRAF2 results in the activation of MEKK1 [24,37,38]. Indeed, in mouse embryonic stem cells deficient in MEKK1, the requirement of this kinase for IL-1 action has been demonstrated [43]. MEKK1 belongs to the group of MAPKs.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1β and mitogen-activated protein kinase kinase kinase in pancreatic islet beta cells

et al. 2007

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Aims/hypothesis Inappropriate insulin secretion and biosynthesis are hallmarks of beta cell dysfunction and contribute to the progression from a prediabetic state to overt diabetes mellitus. During the prediabetic state, beta cells are exposed to elevated levels of proinflammatory cytokines. In the present study the effect of these cytokines and mitogen-activated protein kinase kinase kinase 1 (MEKK1), which is known to be activated by these cytokines, on human insulin gene (INS) transcription was investigated. Methods Biochemical methods and reporter gene assays were used in a beta cell line and in primary pancreatic islets from transgenic mice. Results IL-1β and MEKK1 specifically inhibited basal and membrane depolarisation and cAMP-induced INS transcription in the beta cell line. Also, in primary islets of reporter gene mice, IL-1β reduced glucose-stimulated INS transcription. A 5′-and 3′-deletion and internal mutation analysis revealed the rat insulin promoter element 3b (RIPE3b) to be a decisive MEKK1-responsive element of the INS. RIPE3b conferred strong transcriptional activity to a heterologous promoter, and this activity was markedly inhibited by MEKK1 and IL-1β. RIPE3b is also known to recruit the transcription factor MafA. We found here that MafA transcription activity is markedly inhibited by MEKK1 and IL-1β. Conclusions/interpretation These data suggest that IL-1β through MEKK1 inhibits INS transcription and does so, at least in part, by decreasing MafA transcriptional activity at the RIPE3b control element. Since inappropriate insulin biosynthesis contributes to beta cell dysfunction, inhibition of MEKK1 might decelerate or prevent progression from a prediabetic state to diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1β and mitogen-activated protein kinase kinase kinase in pancreatic islet beta cells

et al. 2007

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“…38 Defects in MAPK kinase kinase 1 (MEKK1) result in defective migration and proinflammatory response of fibroblasts, epithelial cells, and embryonic stem cells. 39,40 MEKK3 deficiency results in early embryonic lethality due to defective development of blood vessels and yolk sac, indicating an essential role in cardiovascular system development. 41 However, the major defects in these mouse models have precluded examination of adult hematopoiesis and hematopoietic stem cell biology.…”

Section: Discussionmentioning

confidence: 99%

Abnormal hematopoiesis in Gab2 mutant mice

Zhang

Díaz-Flores

et al. 2007

Blood

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Gab2 is an important adapter molecule for cytokine signaling. Despite its major role in signaling by receptors associated with hematopoiesis, the role of Gab2 in hematopoiesis has not been addressed. We report that despite normal numbers of peripheral blood cells, bone marrow cells, and c-Kit ؉ Lin ؊ Sca-1 ؉ (KLS) cells, Gab2-deficient hematopoietic cells are deficient in cytokine responsiveness. Significant reductions in the number of colonyforming units in culture (CFU-C) in the presence of limiting cytokine concentrations were observed, and these defects could be completely corrected by retroviral complementation. In earlier hematopoiesis, Gab2-deficient KLS cells isolated in vitro responded poorly to hematopoietic growth factors, resulting in an up to 11-fold reduction in response to a cocktail of stem cell factor, flt3 ligand, and thrombopoietin. Gab2-deficient c-Kit ؉ Lin ؊ cells also demonstrate impaired activation of extracellular signal-regulated kinase (ERK) and S6 in response to IL-3, which supports defects in activating the phosphatidylinositol-3 kinase (PI-3K) and mitogen-associated protein kinase (MAPK) IntroductionOne of the most prominent motifs in signaling molecules is the Src homology-2 (SH2) domain found in JAKs, signal transducers and activators of transcription (STATs), Grb2, p85, Shc, and others. These SH2 domains are able to bind and "dock" with the phosphorylated tyrosine residues that are common in signal transduction pathways. Multiple protein-binding motifs are present in many of the adapter molecules, leading to multimeric complexes that may also include CrkL, PLC, SHIP, and SHP-2. The Grb2-associated binding protein (Gab) family of adapter proteins (Gab1, Gab2, Gab3) include a family of scaffolding/docking/adapter molecules involved in multiple signaling pathways, including the phosphatidylinositol-3 kinase (PI-3K) and mitogen-associated protein kinase (MAPK) pathways, and include multiple proteinbinding sites. [1][2][3] These proteins are tyrosine phosphorylated following cytokine stimulation and are able to interact with a large number of partners. The mechanisms that confer specificity in directing which interactions occur in any particular cell type upon cytokine stimulation remain to be determined. Gab1 deficiency results in embryonic lethality, and conditional deletion of Gab1 shows a role for Gab1 in promoting extracellular signal-regulated kinase (ERK) activation in hepatic function. 4,5 Gab1 acts as an adapter protein to link gp130 signaling to the ERK pathway. 6 In contrast, Gab3 knockout mice do not show major phenotypes. 2 Gab2 is tyrosine phosphorylated by several early-acting cytokine receptors such as flt3, c-Kit, IL-3R, and c-Mpl, and contains proline-rich and pleckstrin homology (PH) domains that promote binding to signaling molecules. 1,7,8 This cytokine activation profile is very similar to STAT5. Gab2 activates the PI-3K and MAPK pathways and can regulate hematopoietic cell migration functions. 9 Gab proteins also contain a large number of consensus serine/...

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“…ECSIT binds to TRAF6 and is required for TLR and interleulin-1 (IL-1) signaling, but not TNFsignaling (Kopp et al, 1999;Xiao et al, 2003). Although these studies suggested that ECSIT functions by recruiting and activating the kinase MEKK1 (mitogen activated protein kinase or ERK kinase (MEK) kinase 1) (Kopp et al, 1999;Xiao et al, 2003), the role of MEKK1 in TLR signaling remains unclear (Xia et al, 2000;Yujiri et al, 2000). MEKK3-deficient cells, however, do not transcribe IL-6 following TLR4 or IL-1R stimulation and exhibit delayed and weakened NF-kB DNA binding following lipopolysaccharide (LPS) stimulation (Huang et al, 2004).…”

Section: Toll-like Receptorsmentioning

confidence: 99%