Genomes and Genes
map kinase kinase kinase 2
Summary: A 70-kDa MAP kinase kinase kinase with specificity for MAP KINASE KINASE 5. It is activated during the cellular response to GROWTH FACTORS, oxidative stress, and hyperosmotic conditions.
- Maruyama T, Kadowaki H, Okamoto N, Nagai A, Naguro I, Matsuzawa A, et al. CHIP-dependent termination of MEKK2 regulates temporal ERK activation required for proper hyperosmotic response. EMBO J. 2010;29:2501-14 pubmed publisher..These findings show that transient activation of the ERK pathway, which depends not only on MEKK2 activation, but also on CHIP-dependent MEKK2 degradation, is crucial for proper gene expression in hyperosmotic stress response. ..
- Su B, Cheng J, Yang J, Guo Z. MEKK2 is required for T-cell receptor signals in JNK activation and interleukin-2 gene expression. J Biol Chem. 2001;276:14784-90 pubmed..Taken together, our results showed that human MEKK2 is a key signaling molecule for T-cell receptor/CD3-mediated JNK MAPK activation and interleukin-2 gene expression. ..
- Chayama K, Papst P, Garrington T, Pratt J, Ishizuka T, Webb S, et al. Role of MEKK2-MEK5 in the regulation of TNF-alpha gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells. Proc Natl Acad Sci U S A. 2001;98:4599-604 pubmed..These findings suggest that JNK activation by antigen cross-linking is dependent on the MEKK2-MKK7 pathway, and cytokine production in mast cells is regulated in part by the signaling complex MEKK2-MEK5-ERK5. ..
- Garrington T, Ishizuka T, Papst P, Chayama K, Webb S, Yujiri T, et al. MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells. EMBO J. 2000;19:5387-95 pubmed..MEKK2 is the first MAP3K shown to be required for mast cell tyrosine kinase receptor signaling controlling cytokine gene expression. ..
- Choi M, Cohen T, Barrientos T, Wang B, Li M, Simmons B, et al. A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Mol Cell. 2012;47:122-32 pubmed publisher..Our findings establish an HDAC4-MAPK-AP1 signaling axis essential for neurogenic muscle atrophy and uncover a direct crosstalk between acetylation- and phosphorylation-dependent signaling cascades. ..
- Yamashita M, Ying S, Zhang G, Li C, Cheng S, Deng C, et al. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell. 2005;121:101-13 pubmed..These results indicate that Smurf1 negatively regulates osteoblast activity and response to BMP through controlling MEKK2 degradation. ..
- Matitau A, Gabor T, Gill R, Scheid M. MEKK2 kinase association with 14-3-3 protein regulates activation of c-Jun N-terminal kinase. J Biol Chem. 2013;288:28293-302 pubmed publisher..These results indicate that Thr-283 phosphorylation is an important regulatory mechanism for MEKK2 activation. ..
- Wan L, Zou W, Gao D, Inuzuka H, Fukushima H, Berg A, et al. Cdh1 regulates osteoblast function through an APC/C-independent modulation of Smurf1. Mol Cell. 2011;44:721-33 pubmed publisher..They further suggest that modulation of Cdh1 is a potential therapeutic option for treatment of osteoporosis. ..
- Uhlik M, Abell A, Cuevas B, Nakamura K, Johnson G. Wiring diagrams of MAPK regulation by MEKK1, 2, and 3. Biochem Cell Biol. 2004;82:658-63 pubmed..We propose that signal transduction network wiring diagrams are valuable tools for hypothesis building and filtering physiologically relevant phenotypic responses from less connected protein relations in the regulation of MAPK pathways. ..
- Wei X, Sun W, Fan R, Hahn J, Joetham A, Li G, et al. MEF2C regulates c-Jun but not TNF-alpha gene expression in stimulated mast cells. Eur J Immunol. 2003;33:2903-9 pubmed
- Rahaman S, Lennon D, Febbraio M, Podrez E, Hazen S, Silverstein R. A CD36-dependent signaling cascade is necessary for macrophage foam cell formation. Cell Metab. 2006;4:211-21 pubmed..These findings show that a specific CD36-dependent signaling pathway initiated by oxLDL is necessary for foam cell formation and identify potential targets for antiatherosclerosis therapy. ..
- Dangi S, Chen F, Shapiro P. Activation of extracellular signal-regulated kinase (ERK) in G2 phase delays mitotic entry through p21CIP1. Cell Prolif. 2006;39:261-79 pubmed
- Mazur P, Reynoird N, Khatri P, Jansen P, Wilkinson A, Liu S, et al. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature. 2014;510:283-7 pubmed publisher..Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signalling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signalling. ..
- Abella J, Peschard P, Naujokas M, Lin T, Saucier C, Urbé S, et al. Met/Hepatocyte growth factor receptor ubiquitination suppresses transformation and is required for Hrs phosphorylation. Mol Cell Biol. 2005;25:9632-45 pubmed
- Datto M, Wang X. Ubiquitin-mediated degradation a mechanism for fine-tuning TGF-beta signaling. Cell. 2005;121:2-4 pubmed..The first paper identifies and characterizes a novel Smad4 ubiquitin ligase, and the second paper redefines the role of a previously identified Smad1 ubiquitin ligase, Smurf-1 (Dupont et al., 2005; Yamashita et al., 2005). ..
- Wang Y, Su B, Xia Z. Brain-derived neurotrophic factor activates ERK5 in cortical neurons via a Rap1-MEKK2 signaling cascade. J Biol Chem. 2006;281:35965-74 pubmed..This study identifies Rap1 and MEKK2 as critical upstream signaling molecules mediating BDNF stimulation of ERK5 in central nervous system neurons. ..
- Nakamura K, Johnson G. Noncanonical function of MEKK2 and MEK5 PB1 domains for coordinated extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase signaling. Mol Cell Biol. 2007;27:4566-77 pubmed
- Qiu L, Ding L, Huang J, Wang D, Zhang J, Guo B. Induction of copper/zinc-superoxide dismutase by CCL5/CCR5 activation causes tumour necrosis factor-alpha and reactive oxygen species production in macrophages. Immunology. 2009;128:e325-34 pubmed publisher..These data suggest that SOD-1 mediates CCR5 activation by CCL5 and that pharmacological modulation of SOD-1 may be beneficial to CCR5-associated diseases. ..
- Nakamura K, Johnson G. Activity assays for extracellular signal-regulated kinase 5. Methods Mol Biol. 2010;661:91-106 pubmed publisher..ERK5 is also critical for maintenance of vascular integrity and endothelial cell survival. In this chapter, we define methods used to measure the activation of ERK5 using different biochemical and cell-based assays. ..
- 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
- 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. ..
- Sah N, Munshi A, Kurland J, McDonnell T, Su B, Meyn R. Translation inhibitors sensitize prostate cancer cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by activating c-Jun N-terminal kinase. J Biol Chem. 2003;278:20593-602 pubmed..However, in addition to JNK activation, other aspects of translation inhibition such as the suppressed activity of apoptosis-inhibitory proteins or activation of other signal transduction pathways must also be involved. ..
- Cheng J, Yu L, Zhang D, Huang Q, Spencer D, Su B. Dimerization through the catalytic domain is essential for MEKK2 activation. J Biol Chem. 2005;280:13477-82 pubmed..Together, these results suggest a novel mechanism underlying MEKK2 regulation and activation. ..
- Ahmad S, Hughes M, Johnson G, Scott J. Development and validation of a high-throughput intrinsic ATPase activity assay for the discovery of MEKK2 inhibitors. J Biomol Screen. 2013;18:388-99 pubmed publisher..Thus, this assay has utility for the discovery of small-molecule inhibitors of MEKK2 activity. ..
- Hehlgans S, Eke I, Cordes N. Targeting FAK radiosensitizes 3-dimensional grown human HNSCC cells through reduced Akt1 and MEK1/2 signaling. Int J Radiat Oncol Biol Phys. 2012;83:e669-76 pubmed publisher..These data strongly support our hypothesis that FAK is a relevant molecular target for HNSCC radiotherapy. ..
- Moran S, Haider K, Ow Y, Milton P, Chen L, Pillai S. Protein kinase C-associated kinase can activate NFkappaB in both a kinase-dependent and a kinase-independent manner. J Biol Chem. 2003;278:21526-33 pubmed..Taken together, these data indicate that PKK may function in both a kinase-dependent as well as a kinase-independent manner to activate NFkappaB. ..
- 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. ..
- Zhang S, Li Z, Wu X, Huang Q, Shen H, Ong C. Methyl-3-indolylacetate inhibits cancer cell invasion by targeting the MEK1/2-ERK1/2 signaling pathway. Mol Cancer Ther. 2006;5:3285-93 pubmed..In conclusion, data from this study provided new insight into the anticancer potential of MIA, a cruciferous vegetable-derived indole compound. ..
- 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. ..
- Cheng J, Yang J, Xia Y, Karin M, Su B. Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation. Mol Cell Biol. 2000;20:2334-42 pubmed..Thus, formation of a signaling complex through synergistic interaction of a MAPKKK, a MAPKK, and a MAPK molecule like MEKK2-JNKK2-JNK1 is likely to be responsible for the efficient, specific flow of information via MAPK cascades. ..
- Sun W, Vincent S, Settleman J, Johnson G. MEK kinase 2 binds and activates protein kinase C-related kinase 2. Bifurcation of kinase regulatory pathways at the level of an MAPK kinase kinase. J Biol Chem. 2000;275:24421-8 pubmed..MEKK2 activation of PRK2 is independent of MEKK2 regulation of the c-Jun NH(2)-terminal kinase pathway. MEKK2 activation of PRK2 results in a bifurcation of signaling for the dual control of MAPK pathways and PRK2 regulated responses. ..
- Widmann C, Sather S, Oyer R, Johnson G, Dreskin S. In vitro activity of MEKK2 and MEKK3 in detergents is a function of a valine to serine difference in the catalytic domain. Biochim Biophys Acta. 2001;1547:167-73 pubmed..The presence of a serine or threonine adjacent to the active site lysine in protein kinases is rare and, in MEKK3, results in detergent instability. ..
- Kane L, Lin J, Weiss A. It's all Rel-ative: NF-kappaB and CD28 costimulation of T-cell activation. Trends Immunol. 2002;23:413-20 pubmed..Although many questions remain, recent years have witnessed significant progress in understanding the signal transduction pathways leading from the TCR and CD28 to Rel/NF-kappaB-dependent transcription. ..
- 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. ..
- Yamauchi J, Takai S, Matsushima Nishiwaki R, Hanai Y, Doi T, Kato H, et al. (-)-epigallocatechin gallate inhibits prostaglandin D2-stimulated HSP27 induction via suppression of the p44/p42 MAP kinase pathway in osteoblasts. Prostaglandins Leukot Essent Fatty Acids. 2007;77:173-9 pubmed..However, the PGD2-induced phosphorylation of Raf-1 was not inhibited by EGCG. These results strongly suggest that EGCG suppresses the PGD2-stimulated induction of HSP27 at the point between Raf-1 and MEK1/2 in osteoblasts. ..
- Kang U, Koo Y, Jeon W, Park D, Juhnn Y, Park J, et al. Activation of extracellular signal-regulated kinase signaling by chronic electroconvulsive shock in the rat frontal cortex. Psychiatry Res. 2006;145:75-8 pubmed..Thereafter, a plateau was achieved. The expression of brain-derived neurotrophic factor was continuously increased for 10 days. Our data show that the effect of ECS on ERK1/2 signaling is increased with chronic treatment. ..
- Kihara S, Yamamoto H, Ohba T, Shimasaki S, Okamura H. Activation of follistatin promoter by GnRH in LbetaT2 gonadotroph cells. Endocr J. 2006;53:225-35 pubmed..These results suggest that the activations of both the protein kinase C and tyrosine kinase pathways are necessary for the activation of the FS promoter in gonadotroph cells. ..
- Schmidt C, Peng B, Li Z, Sclabas G, Fujioka S, Niu J, et al. Mechanisms of proinflammatory cytokine-induced biphasic NF-kappaB activation. Mol Cell. 2003;12:1287-300 pubmed..These findings provide further insight into the regulation of cytokine-induced specific and temporal gene expression. ..
- Browning J, Patel T, Brandt P, Young K, Holcomb L, Hicks P. Clozapine and the mitogen-activated protein kinase signal transduction pathway: implications for antipsychotic actions. Biol Psychiatry. 2005;57:617-23 pubmed..These data support the hypothesis that the MEK/ERK signal transduction cascade participates in clozapine's antipsychotic actions. ..
- Park J, Powers J, Tischler A, Strock C, Ball D, Nelkin B. GDNF-induced leukemia inhibitory factor can mediate differentiation via the MEK/ERK pathway in pheochromocytoma cells derived from nf1-heterozygous knockout mice. Exp Cell Res. 2005;303:79-88 pubmed..Our findings suggest that LIF may be utilized for signaling mediated by GDNF and may be important in the pathobiology of neuroendocrine tumors. ..
- Su S, Bush S, Zaman N, Stecker K, Sussman M, Krysan P. Deletion of a tandem gene family in Arabidopsis: increased MEKK2 abundance triggers autoimmunity when the MEKK1-MKK1/2-MPK4 signaling cascade is disrupted. Plant Cell. 2013;25:1895-910 pubmed publisher..In turn, the abundance of MEKK2 appears to be under cellular surveillance such that a modest increase can trigger defense response activation. ..
- Ho D, Bardwell A, Grewal S, Iverson C, Bardwell L. Interacting JNK-docking sites in MKK7 promote binding and activation of JNK mitogen-activated protein kinases. J Biol Chem. 2006;281:13169-79 pubmed..We conclude that MKK7 contains three JNK-docking sites that interact to selectively bind JNK and contribute to JNK signal transmission and specificity. ..
- Nicholas H, Hodgkin J. The ERK MAP kinase cascade mediates tail swelling and a protective response to rectal infection in C. elegans. Curr Biol. 2004;14:1256-61 pubmed..elegans from severe constipation, which would otherwise arrest development and cause sterility. Involvement in pathogen defense represents a new role for ERK MAP kinase signaling in this organism. ..
- Kong G, Zhang J, Zhang S, Shan C, Ye L, Zhang X. Hepatitis B virus X protein promotes hepatoma cell proliferation via upregulation of MEKK2. Acta Pharmacol Sin. 2011;32:1173-80 pubmed publisher..In 95 clinical HCC tissues, the rate of detection of MEKK2 was 85.3%. HBx promotes hepatoma cell proliferation via upregulating MEKK2, which may be involved in hepatocarcinogenesis...
- Chang X, Liu F, Wang X, Lin A, Zhao H, Su B. The kinases MEKK2 and MEKK3 regulate transforming growth factor-?-mediated helper T cell differentiation. Immunity. 2011;34:201-12 pubmed publisher..Thus, the crosstalk between TCR-induced MAPK and the TGF-? signaling pathways is important in regulating Th cell differentiation. ..
- Yao Z, Yoon S, Kalie E, Raviv Z, Seger R. Calcium regulation of EGF-induced ERK5 activation: role of Lad1-MEKK2 interaction. PLoS ONE. 2010;5:e12627 pubmed publisher..Taken together, these findings suggest that calcium is required for EGF-induced ERK5 activation, and this effect is probably mediated by securing proper interaction of MEKK2 with the upstream adaptor protein Lad1. ..
- Lin S, Kok S, Shun C, Hong C, Wang C, Hsu M, et al. Tumor necrosis factor-alpha stimulates the expression of C-C chemokine ligand 2 gene in fibroblasts from the human nasal polyp through the pathways of mitogen-activated protein kinase. Am J Rhinol. 2007;21:251-5 pubmed..TNF-alpha induces CCL2 transcription in NPFs. B-Raf/MEK/ERK signaling cascade and to a less extent the p38 pathway are responsible for c-Fos activation and the subsequent AP-1/DNA interaction leading to CCL2 expression. ..
- Ziera T, Irlbacher H, Fromm A, Latouche C, Krug S, Fromm M, et al. Cnksr3 is a direct mineralocorticoid receptor target gene and plays a key role in the regulation of the epithelial sodium channel. FASEB J. 2009;23:3936-46 pubmed publisher..We conclude that CNKSR3, a homologue of scaffold proteins involved in MAPK pathway regulation, is a direct target of MR and is required for the maintenance of transepithelial sodium transport in the kidney. ..
- Brown R, Ambler S, Li M, Sullivan T, Henry L, Crossno J, et al. MAP kinase kinase kinase-2 (MEKK2) regulates hypertrophic remodeling of the right ventricle in hypoxia-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2013;304:H269-81 pubmed publisher..Therapies targeting MEKK2 may protect the myocardium from hypertrophy and pathological remodeling in human PH. ..
- Zhang D, Facchinetti V, Wang X, Huang Q, Qin J, Su B. Identification of MEKK2/3 serine phosphorylation site targeted by the Toll-like receptor and stress pathways. EMBO J. 2006;25:97-107 pubmed..In conclusion, this study reveals a novel molecular mechanism for MEKK2/3 activation by the TLR and cellular stress pathways. ..
- Weyerbacher A, Xu Q, Tamasdan C, Shin S, Inturrisi C. N-Methyl-D-aspartate receptor (NMDAR) independent maintenance of inflammatory pain. Pain. 2010;148:237-46 pubmed publisher..Effective reduction of the initiation and maintenance of inflammatory pain requires targeting the neuron-astrocyte-cytokine interactions revealed in these studies. ..
- Stollenwerk M, Schiopu A, Fredrikson G, Dichtl W, Nilsson J, Ares M. Very low density lipoprotein potentiates tumor necrosis factor-alpha expression in macrophages. Atherosclerosis. 2005;179:247-54 pubmed..These findings suggest that triacylglycerol-rich lipoproteins are involved in inflammatory processes associated with atherosclerosis. ..