Genomes and Genes
map kinase kinase kinase 4
Summary: A 180-kDa MAP kinase kinase kinase with specificity for MAP KINASE KINASE 4 and MAP KINASE KINASE 6.
- Chi H, Lu B, Takekawa M, Davis R, Flavell R. GADD45beta/GADD45gamma and MEKK4 comprise a genetic pathway mediating STAT4-independent IFNgamma production in T cells. EMBO J. 2004;23:1576-86 pubmed..During Th1 differentiation, the GADD45beta/GADD45gamma/MEKK4 pathway appears to integrate upstream signals transduced by both T cell receptor and IL12/STAT4, leading to augmented IFNgamma production in a process independent of STAT4. ..
- Chi H, Sarkisian M, Rakic P, Flavell R. Loss of mitogen-activated protein kinase kinase kinase 4 (MEKK4) results in enhanced apoptosis and defective neural tube development. Proc Natl Acad Sci U S A. 2005;102:3846-51 pubmed..Here, we show that MAP kinase kinase kinase 4 (MEKK4) is strongly expressed in the developing neuroepithelium...
- Miyake Z, Takekawa M, Ge Q, Saito H. Activation of MTK1/MEKK4 by GADD45 through induced N-C dissociation and dimerization-mediated trans autophosphorylation of the MTK1 kinase domain. Mol Cell Biol. 2007;27:2765-76 pubmed..Constitutively active MTK1 mutants induced the same events, but in the absence of GADD45. ..
- Sollome J, Thavathiru E, Camenisch T, Vaillancourt R. HER2/HER3 regulates extracellular acidification and cell migration through MTK1 (MEKK4). Cell Signal. 2014;26:70-82 pubmed publisher..Cell migration is required for cancer cell metastasis, which is the major cause of cancer patient mortality. We identify MTK1 in the HER2/HER3-HRG mediated extracellular acidification and cell migration pathway in breast cancer cells. ..
- Warr N, Carré G, Siggers P, Faleato J, Brixey R, Pope M, et al. Gadd45? and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression. Dev Cell. 2012;23:1020-31 pubmed publisher..Taken together, our data suggest a requirement for GADD45? in promoting MAP3K4-mediated activation of p38 MAPK signaling in embryonic gonadal somatic cells for testis determination in the mouse. ..
- Clark N, Marinis J, Cobb B, Abbott D. MEKK4 sequesters RIP2 to dictate NOD2 signal specificity. Curr Biol. 2008;18:1402-8 pubmed publisher..These biochemical findings suggest that basal inhibition of the NOD2-driven NFkappaB pathway by MEKK4 could be important in the pathogenesis of Crohn's disease. ..
- Derbyshire Z, Halfter U, Heimark R, Sy T, Vaillancourt R. Angiotensin II stimulated transcription of cyclooxygenase II is regulated by a novel kinase cascade involving Pyk2, MEKK4 and annexin II. Mol Cell Biochem. 2005;271:77-90 pubmed
- Weizman N, Shiloh Y, Barzilai A. Contribution of the Atm protein to maintaining cellular homeostasis evidenced by continuous activation of the AP-1 pathway in Atm-deficient brains. J Biol Chem. 2003;278:6741-7 pubmed..Our results further demonstrate that inactivation of the ATM gene results in a state of constant stress. ..
- Huang J, Tu Z, Lee F. Mutations in protein kinase subdomain X differentially affect MEKK2 and MEKK1 activity. Biochem Biophys Res Commun. 2003;303:532-40 pubmed..Interestingly, the spectrum of mutations in subdomain X of MEKK2 that affects its activity is overlapping with but not identical to those that have effects on MEKK1. Thus, mutations in subdomain X differentially affect MEKK2 and MEKK1. ..
- Homer C, Kabi A, Marina Garcia N, Sreekumar A, Nesvizhskii A, Nickerson K, et al. A dual role for receptor-interacting protein kinase 2 (RIP2) kinase activity in nucleotide-binding oligomerization domain 2 (NOD2)-dependent autophagy. J Biol Chem. 2012;287:25565-76 pubmed publisher..RIP2 both sends a positive autophagy signal through activation of p38 MAPK and relieves repression of autophagy mediated by the phosphatase PP2A. ..
- Mizote I, Yamaguchi O, Hikoso S, Takeda T, Taneike M, Oka T, et al. Activation of MTK1/MEKK4 induces cardiomyocyte death and heart failure. J Mol Cell Cardiol. 2010;48:302-9 pubmed publisher..Thus, MTK1 plays an important role in the regulation of cell death and is also involved in the pathogenesis of heart failure. ..
- Gordon P, Soliman M, Bose P, Trinh Q, Sensen C, Riabowol K. Interspecies data mining to predict novel ING-protein interactions in human. BMC Genomics. 2008;9:426 pubmed publisher..We therefore propose that the weak (low signal to noise ratio) data from large-scale interaction datasets are currently underutilized. ..
- Andreone T, O Connor M, Denenberg A, Hake P, Zingarelli B. Poly(ADP-ribose) polymerase-1 regulates activation of activator protein-1 in murine fibroblasts. J Immunol. 2003;170:2113-20 pubmed..No DNA binding of heat shock factor-1 was observed in PARP-1-deficient cells. These data demonstrate that PARP-1 plays a pivotal role in the modulation of transcription. ..
- Luo W, Ng W, Jin L, Ye Z, Han J, Lin S. Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation. J Biol Chem. 2003;278:37451-8 pubmed..Our findings will provide new insights into how scaffold proteins mediate ultimate activation of different mitogen-activated protein kinase kinase kinases. ..
- Mita H, Tsutsui J, Takekawa M, Witten E, Saito H. Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding. Mol Cell Biol. 2002;22:4544-55 pubmed..These MTK1 mutants are constitutively active, in both yeast and mammalian cells. A model of MTK1 autoinhibition by the N-terminal inhibitory domain and activation by GADD45 binding is presented. ..
- Stevens M, Parker P, Vaillancourt R, Camenisch T. MEKK4 regulates developmental EMT in the embryonic heart. Dev Dyn. 2006;235:2761-70 pubmed..Thus, the kinase activity of MEKK4 is essential, but not sufficient, to support developmental EMT. This knowledge provides a basis to understand how MEKK4 may integrate signaling cascades controlling heart development. ..
- van der Pouw Kraan C, Baggen J, van Bodegraven A, Mulder C, Zwiers A, Geerts D, et al. Defective IL-1A expression in patients with Crohn's disease is related to attenuated MAP3K4 signaling. Hum Immunol. 2012;73:912-9 pubmed publisher..This confirms the hypothesis that CD patients, despite their massive intestinal inflammation, suffer from a relative immune deficiency in TLR-mediated cytokine production. ..
- Yang J, Zhu H, Murphy T, Ouyang W, Murphy K. IL-18-stimulated GADD45 beta required in cytokine-induced, but not TCR-induced, IFN-gamma production. Nat Immunol. 2001;2:157-64 pubmed..Thus, the synergy between IL-12 and IL-18 may involve GADD45 beta induction, which can maintain the MEKK4 and p38 MAPK activation that is necessary for cytokine-induced, but not TCR-induced, IFN-gamma production. ..
- Lee Y, Malbon C, Wang H. G alpha 13 signals via p115RhoGEF cascades regulating JNK1 and primitive endoderm formation. J Biol Chem. 2004;279:54896-904 pubmed..In a concerted effort, RhoA in tandem with Cdc42 and Rac1 activates the MEKK1/4, MEK1/MKK4, and JNK cascade, thereby stimulating formation of primitive endoderm. ..
- Bonvin C, Guillon A, van Bemmelen M, Gerwins P, Johnson G, Widmann C. Role of the amino-terminal domains of MEKKs in the activation of NF kappa B and MAPK pathways and in the regulation of cell proliferation and apoptosis. Cell Signal. 2002;14:123-31 pubmed..Our data show that the N-terminal domain of the MEKKs determines the specificity and the strength of activation of various intracellular signaling pathways and cellular responses. ..
- Tsuchimochi K, Otero M, Dragomir C, Plumb D, Zerbini L, Libermann T, et al. GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes. J Biol Chem. 2010;285:8395-407 pubmed publisher..Collectively, we have uncovered a novel molecular mechanism linking GADD45beta via the MTK1/MKK3/6/p38 axis to C/EBPbeta-TAD4 activation of Col10a1 transcription in terminally differentiating chondrocytes. ..
- Kedar V, Darby M, Williams J, Blackshear P. Phosphorylation of human tristetraprolin in response to its interaction with the Cbl interacting protein CIN85. PLoS ONE. 2010;5:e9588 pubmed publisher..The functional consequences to each of the members of this putative complex remain to be determined. ..
- Grucza R, Johnson E, Krueger R, Breslau N, Saccone N, Chen L, et al. Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes. Addict Biol. 2010;15:346-57 pubmed publisher..Incorporation of logically chosen interaction parameters, such as AOS, into genetic models of substance use disorders may increase the degree of explained phenotypic variation and constitutes a promising avenue for gene discovery. ..
- Abell A, Granger D, Johnson G. MEKK4 stimulation of p38 and JNK activity is negatively regulated by GSK3beta. J Biol Chem. 2007;282:30476-84 pubmed..Thus, control of MEKK4 dimerization is regulated both positively and negatively by its interaction with specific proteins. ..
- Sun B, Kim J, Nguyen H, Oh S, Kim S, Choi S, et al. MEKK1/MEKK4 are responsible for TRAIL-induced JNK/p38 phosphorylation. Oncol Rep. 2011;25:537-44 pubmed publisher..Taken together, we show herein that the upstream molecule of the TRAIL-induced MAPK activation is MEKK, as opposed to ASK1, via the mediation of its signal through JNK/p38 in a caspase-8-dependent manner. ..
- Keil E, Höcker R, Schuster M, Essmann F, Ueffing N, Hoffman B, et al. Phosphorylation of Atg5 by the Gadd45?-MEKK4-p38 pathway inhibits autophagy. Cell Death Differ. 2013;20:321-32 pubmed publisher..Thus, we show for the first time that Atg5 activity is controlled by phosphorylation and, moreover, that the spatial regulation of p38 by Gadd45?/MEKK4 negatively regulates the autophagic process. ..
- Champion A, Picaud A, Henry Y. Reassessing the MAP3K and MAP4K relationships. Trends Plant Sci. 2004;9:123-9 pubmed
- Ray R, Jin S, Bavaria M, Johnson L. Regulation of JNK activity in the apoptotic response of intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2011;300:G761-70 pubmed publisher..Taken together, these results suggest that MKP1 activity determines the duration of JNK1/2 and p38 activation and, thereby, apoptosis in response to TNF + CPT. ..
- Wang H, Kanungo J, Malbon C. Expression of Galpha 13 (Q226L) induces P19 stem cells to primitive endoderm via MEKK1, 2, or 4. J Biol Chem. 2002;277:3530-6 pubmed
- Kim J, Kang D, Sun B, Kim J, Song J. TRAIL/MEKK4/p38/HSP27/Akt survival network is biphasically modulated by the Src/CIN85/c-Cbl complex. Cell Signal. 2013;25:372-9 pubmed publisher..Taken together, these data demonstrate that phosphorylated p38/HSP27 as biphasic modulators act in conjunction with CIN85 to determine whether cells survive or die in response to apoptotic stress. ..
- Owen G, Achilonu I, Dirr H. High yield purification of JNK1?1 and activation by in vitro reconstitution of the MEKK1?MKK4?JNK MAPK phosphorylation cascade. Protein Expr Purif. 2013;87:87-99 pubmed publisher..Activated JNK1?1 was thereafter able to phosphorylate ATF2 with high catalytic efficiency. ..
- Hagemann C, Blank J. The ups and downs of MEK kinase interactions. Cell Signal. 2001;13:863-75 pubmed..This review summarises our current knowledge concerning the regulation and function of MEKK family members, with particular emphasis on those factors capable of directly interacting with distinct MEKK isoforms. ..
- Abell A, Granger D, Johnson N, Vincent Jordan N, Dibble C, Johnson G. Trophoblast stem cell maintenance by fibroblast growth factor 4 requires MEKK4 activation of Jun N-terminal kinase. Mol Cell Biol. 2009;29:2748-61 pubmed publisher..Our results define MEKK4 as a signaling hub for FGF4 activation of JNK that is required for maintenance of TS cells in an undifferentiated state. ..
- Takagaki K, Satoh T, Tanuma N, Masuda K, Takekawa M, Shima H, et al. Characterization of a novel low-molecular-mass dual-specificity phosphatase-3 (LDP-3) that enhances activation of JNK and p38. Biochem J. 2004;383:447-55 pubmed..4 M sorbitol. By screening with a variety of stimuli, we found that LDP-3 specifically enhances the osmotic stress-induced activation of JNK and p38. ..
- Halfter U, Derbyshire Z, Vaillancourt R. Interferon-gamma-dependent tyrosine phosphorylation of MEKK4 via Pyk2 is regulated by annexin II and SHP2 in keratinocytes. Biochem J. 2005;388:17-28 pubmed..Furthermore, we provide evidence that SHP2 dephosphorylates MEKK4 and Pyk2, terminating the MEKK4-dependent branch of the IFNgamma signalling pathway. ..
- Akiyama S, Yonezawa T, Kudo T, Li M, Wang H, Ito M, et al. Activation mechanism of c-Jun amino-terminal kinase in the course of neural differentiation of P19 embryonic carcinoma cells. J Biol Chem. 2004;279:36616-20 pubmed..These results suggest that two distinct TAK1-MKK4-JNK signaling pathways are independently activated at the different intracellular locations and may participate in the regulation of the neural differentiation of P19 cells. ..
- Ryabinina O, Subbian E, Iordanov M. D-MEKK1, the Drosophila orthologue of mammalian MEKK4/MTK1, and Hemipterous/D-MKK7 mediate the activation of D-JNK by cadmium and arsenite in Schneider cells. BMC Cell Biol. 2006;7:7 pubmed..D-MEKK1, the fly orthologue of mammalian MEKK4/MTK1, and Hemipterous/D-MKK7 mediates the activation of D-JNK by cadmium and arsenite. ..
- Padda R, Wamsley Davis A, Gustin M, Ross R, Yu C, Sheikh Hamad D. MEKK3-mediated signaling to p38 kinase and TonE in hypertonically stressed kidney cells. Am J Physiol Renal Physiol. 2006;291:F874-81 pubmed..Our data are consistent with the existence of an input from MEKK3 -->--> p38 kinase -->--> TonE. ..
- Sarkisian M, Bartley C, Rakic P. Trouble making the first move: interpreting arrested neuronal migration in the cerebral cortex. Trends Neurosci. 2008;31:54-61 pubmed publisher..Elucidating the basic functions of FLNa and associated molecules is crucial for understanding the causes of PH and for developing prevention for at-risk patients. ..
- Delgado M. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in endotoxin-activated microglia. Biochem Biophys Res Commun. 2002;293:771-6 pubmed..The VIP/PACAP interference with the stress-induced SAPK/JNK pathway in activated microglia may represent a significant element in the regulation of inflammatory response in the CNS by endogenous neuropeptides. ..
- Jordan N, Johnson G, Abell A. Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle. 2011;10:2865-73 pubmed..This intersection between EMT and stemness in TS cells and claudin-low metastatic breast cancer demonstrates the usefulness of developmental EMT systems to understand EMT in cancer. ..
- Wei J, Chu C, Wang Y, Yang Y, Wang Q, Li T, et al. Association study of 45 candidate genes in nicotine dependence in Han Chinese. Addict Behav. 2012;37:622-6 pubmed publisher..Furthermore, we for the first time report a significant association between nicotine dependence and DRD5, MAP3K4 and NPY1R. These findings need independent replication in the future studies. ..
- Chan Hui P, Weaver R. Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades. Biochem J. 1998;336 ( Pt 3):599-609 pubmed..Differences in the reported functional activities of the three kinases are discussed. ..
- Suetsugu S, Takenawa T. Stress-associated MAP kinase fills in the map of filamin-mediated neuronal migration. Dev Cell. 2007;12:3-4 pubmed
- Ricote M, Royuela M, García Tuñón I, Bethencourt F, Paniagua R, Fraile B. Pro-apoptotic tumor necrosis factor-alpha transduction pathway in normal prostate, benign prostatic hyperplasia and prostatic carcinoma. J Urol. 2003;170:787-90 pubmed..In prostate cancer this pathway is probably inactivated by other factors, such as p21 (at the ASK-1 level) or bcl-2 (at the JNK level). ..
- Lotan T, Lyon M, Huo D, Taxy J, Brendler C, Foster B, et al. Up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression: an important role for SAPK signalling in prostatic neoplasia. J Pathol. 2007;212:386-94 pubmed..The finding that higher MKK4 and MKK7 expression is associated with higher-stage prostatic tumours underscores the dynamic regulation of these proteins during prostatic tumourigenesis. ..
- Kawahara A, Che Y, Hanaoka R, Takeda H, Dawid I. Zebrafish GADD45beta genes are involved in somite segmentation. Proc Natl Acad Sci U S A. 2005;102:361-6 pubmed..These results indicate that regulated expression of gadd45beta genes in the anterior PSM is required for somite segmentation...
- Wong C, Luo W, Deng Y, Zou H, Ye Z, Lin S. The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase activation by Axin and dishevelled through distinct mechanisms. J Biol Chem. 2004;279:39366-73 pubmed
- Liu H, Zhang H, Iles K, Rinna A, Merrill G, Yodoi J, et al. The ADP-stimulated NADPH oxidase activates the ASK-1/MKK4/JNK pathway in alveolar macrophages. Free Radic Res. 2006;40:865-74 pubmed