MEK kinase 1 gene disruption alters cell migration and c-Jun NH
            <sub>2</sub>
            -terminal kinase regulation but does not cause a measurable defect in NF-κB activation

Yujiri, Toshiaki; Ware, Margaret F.; Widmann, Christian; Oyer, Ryan; Russell, D. M.; Chan, Edward D.; Zaitsu, Yuzuru; Clarke, Penny; Tyler, Kenneth L.; Oka, Yoshitomo; Fanger, Gary R.; Henson, Peter M.; Johnson, Gary L.

doi:10.1073/pnas.130176697

Cited by 227 publications

(190 citation statements)

References 28 publications

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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%

NF-κB and the immune response

2006

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Section: Toll-like Receptorsmentioning

confidence: 99%

NF-κB and the immune response

2006

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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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“…Mice lacking either the full-length MAP3K1 protein (MAP3K1-null or Map3k1(−/−)) or its kinase domain (Map3k1(ΔKD/ΔKD)) survive embryonic development and do not show overt developmental defects except for an "eyeopen at birth" (EOB) phenotype (Yujiri et al, 2000;Zhang et al, 2003).…”

Section: Map3k1 In Ocular Surface Developmentmentioning

confidence: 99%

“…Activation of the MAP3K1-JNK cascade promotes epithelial cell migration, which is required for the developing eyelid tip epithelial cells to move forward for eyelid closure (Yujiri et al, 2000;Zhang et al, 2003). One downstream event of the MAP3K1-JNK axis is the phosphorylation of c-Jun at its Nterminus, which leads to increased AP-1 activity and enhanced expression of AP-1 target genes, such as PAI-1 (Zhang et al, 2003;Takatori et al, 2008;Geh et al, 2011).…”

Section: The Map3k1-c-jun Intracrine Regulatory Loop For Eyelid Morphmentioning

confidence: 99%