map kinase kinase kinase 3


Summary: A 70-kDa MAPK kinase kinase with specificity for MAP KINASE KINASE 5.

Top Publications

  1. Huang Q, Yang J, Lin Y, Walker C, Cheng J, Liu Z, et al. Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nat Immunol. 2004;5:98-103 pubmed
    ..Note: In the version of this article originally published online, the third author's name was incorrect. The correct author name should be Yong Lin. This error has been corrected for the HTML and print versions of this article. ..
  2. Abbasi S, Su B, Kellems R, Yang J, Xia Y. The essential role of MEKK3 signaling in angiotensin II-induced calcineurin/nuclear factor of activated T-cells activation. J Biol Chem. 2005;280:36737-46 pubmed
    ..Taken together, our studies reveal a previously unrecognized novel essential regulatory role of MEKK3 signaling in calcineurin/NFAT activation. ..
  3. 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. ..
  4. Wang A, Nomura M, Patan S, Ware J. Inhibition of protein kinase Calpha prevents endothelial cell migration and vascular tube formation in vitro and myocardial neovascularization in vivo. Circ Res. 2002;90:609-16 pubmed
  5. Le Niculescu H, Levey D, Ayalew M, Palmer L, Gavrin L, Jain N, et al. Discovery and validation of blood biomarkers for suicidality. Mol Psychiatry. 2013;18:1249-64 pubmed publisher
    ..Overall, suicidality may be underlined, at least in part, by biological mechanisms related to stress, inflammation and apoptosis. ..
  6. Sagar D, Lamontagne A, Foss C, Khan Z, Pomper M, Jain P. Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood-brain barrier through paracellular transmigration and ERK activation. J Neuroinflammation. 2012;9:245 pubmed publisher
    ..Overall, these comprehensive studies provide a state-of-the-art view of DCs within the CNS, elucidate their path across the BBB, and highlight potential mechanisms involved in CCL2-mediated DC trafficking. ..
  7. 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. ..
  8. Xu B, Stippec S, Lenertz L, Lee B, Zhang W, Lee Y, et al. WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. J Biol Chem. 2004;279:7826-31 pubmed
    ..Finally, ERK5 activation by epidermal growth factor was attenuated by suppression of WNK1 expression using small interfering RNA. Taken together, these results place WNK1 in the ERK5 MAP kinase pathway upstream of MEKK2/3. ..
  9. Yu L, Su B, Hollomon M, Deng Y, Facchinetti V, Kleinerman E. Vasculogenesis driven by bone marrow-derived cells is essential for growth of Ewing's sarcomas. Cancer Res. 2010;70:1334-43 pubmed publisher
    ..In contrast, siRNA-mediated knockdown of Mekk3 in TC71 Ewing's sarcoma cells had no effect on tumor growth or vessel density. Our findings indicate that vasculogenesis is critical in the expansion of the tumor vascular network. ..

More Information


  1. Nakamura K, Kimple A, Siderovski D, Johnson G. PB1 domain interaction of p62/sequestosome 1 and MEKK3 regulates NF-kappaB activation. J Biol Chem. 2010;285:2077-89 pubmed publisher
    ..The rear end acidic cluster of the p62 PB1 domain is used to organize cytosolic aggregates or speckles-associated TRAF6-p62-MEKK3 complex for control of NF-kappaB activation. ..
  2. Fang S, Fu J, Yuan X, Han C, Shi L, Xin Y, et al. Heat shock protein 90 regulates the stability of MEKK3 in HEK293 cells. Cell Immunol. 2009;259:49-55 pubmed publisher
    ..A selective inhibitor of Hsp90, geldanamycin (GA), shortened MEKK3 half-life, and induced ubiquitination and proteasomal degradation of MEKK3. These results strongly suggested that Hsp90 could work as the molecular chaperone of MEKK3. ..
  3. Yang J, Boerm M, McCarty M, Bucana C, Fidler I, Zhuang Y, et al. Mekk3 is essential for early embryonic cardiovascular development. Nat Genet. 2000;24:309-13 pubmed
    ..We conclude that Mekk3 is necessary for blood vessel development and may be a possible target for drugs that control angiogenesis. ..
  4. Seyfried J, Wang X, Kharebava G, Tournier C. A novel mitogen-activated protein kinase docking site in the N terminus of MEK5alpha organizes the components of the extracellular signal-regulated kinase 5 signaling pathway. Mol Cell Biol. 2005;25:9820-8 pubmed
    ..Altogether these results establish that the N terminus of MEK5alpha is critical for the specific organization of the components of the ERK5 signaling pathway. ..
  5. Bouwmeester T, Bauch A, Ruffner H, Angrand P, Bergamini G, Croughton K, et al. A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol. 2004;6:97-105 pubmed
    ..This systems approach provides significant insight into the logic of the TNF-alpha/NF-kappa B pathway and is generally applicable to other pathways relevant to human disease. ..
  6. Minoda Y, Sakurai H, Kobayashi T, Yoshimura A, Takaesu G. An F-box protein, FBXW5, negatively regulates TAK1 MAP3K in the IL-1beta signaling pathway. Biochem Biophys Res Commun. 2009;381:412-7 pubmed publisher
    ..Conversely, knockdown of FBXW5 resulted in the prolonged activation of TAK1 upon IL-1beta stimulation. These results suggest that FBXW5 negatively regulates TAK1 in the IL-1beta signaling pathway. ..
  7. Nakamura K, Johnson G. PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. J Biol Chem. 2003;278:36989-92 pubmed
    ..The free PB1 domain of MEKK2 or MEKK3 functions effectively to inhibit the ERK5 pathway but not the p38 or JNK pathways, demonstrating the specific and unique requirement of the MEKK2 and MEKK3 PB1 domain in regulating ERK5 activation. ..
  8. 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. ..
  9. 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. ..
  10. Fan Y, Ge N, Wang X, Sun W, Mao R, Bu W, et al. Amplification and over-expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells. J Pathol. 2014;232:75-86 pubmed publisher
  11. Wang X, Chang X, Facchinetti V, Zhuang Y, Su B. MEKK3 is essential for lymphopenia-induced T cell proliferation and survival. J Immunol. 2009;182:3597-608 pubmed publisher
    ..Together, these data suggest that MEKK3 may play a crucial selective role for spMHC-mediated T cell homeostasis. ..
  12. 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. ..
  13. Kook S, Lee H, Chung W, Hwang I, Lee S, Kim B, et al. Cyclic mechanical stretch stimulates the proliferation of C2C12 myoblasts and inhibits their differentiation via prolonged activation of p38 MAPK. Mol Cells. 2008;25:479-86 pubmed
    ..We conclude that p38 kinase, not ERK, is the upstream signal transducer regulating cellular responses to mechanical stretch in skeletal muscle cells. ..
  14. Craig E, Austin A, Vaillancourt R, Barnett J, Camenisch T. TGF?2-mediated production of hyaluronan is important for the induction of epicardial cell differentiation and invasion. Exp Cell Res. 2010;316:3397-405 pubmed publisher
    ..This is an important and novel mechanism showing how TGF?2 and HA signals are integrated to regulate changes in epicardial cell behavior. ..
  15. Hu Q, Shen W, Huang H, Liu J, Zhang J, Huang X, et al. Insight into the binding properties of MEKK3 PB1 to MEK5 PB1 from its solution structure. Biochemistry. 2007;46:13478-89 pubmed
    ..Residues Lys 7 and Arg 5 play important roles in the interaction with MEK5 PB1. Taken together, this study provides new insights into structural details of MEKK3 PB1 and its binding properties with MEK5 PB1. ..
  16. Hilder T, Malone M, Johnson G. Hyperosmotic induction of mitogen-activated protein kinase scaffolding. Methods Enzymol. 2007;428:297-312 pubmed
  17. Otkjaer K, Kragballe K, Johansen C, Funding A, Just H, Jensen U, et al. IL-20 gene expression is induced by IL-1beta through mitogen-activated protein kinase and NF-kappaB-dependent mechanisms. J Invest Dermatol. 2007;127:1326-36 pubmed
    ..IL-20 is assumed to be a key cytokine in the pathogenesis of psoriasis and possibly cancer, and therefore the p38 MAPK, MSK1, and NF-kappaB may be important new molecular targets for the modulation of IL-20 expression in these diseases. ..
  18. Zheng Y, Liu H, Kong Y. miR-188 promotes senescence of lineage-negative bone marrow cells by targeting MAP3K3 expression. FEBS Lett. 2017;591:2290-2298 pubmed publisher
    ..All data reveal that miR-188 induces lin-BMC senescence by targeting MAP3K3 expression, thus, providing new theoretical basis for the prevention and treatment of cardiovascular diseases. ..
  19. Kim K, Duramad O, Qin X, Su B. MEKK3 is essential for lipopolysaccharide-induced interleukin-6 and granulocyte-macrophage colony-stimulating factor production in macrophages. Immunology. 2007;120:242-50 pubmed
    ..In conclusion, this study showed that MEKK3 is a crucial and specific regulator of the proinflammatory cytokines IL-6 and GM-CSF in macrophages and provided a novel method for investigating MEKK3 function in other immune cells. ..
  20. 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. ..
  21. Wang H, Chakrabarty S. Platelet-activating factor activates mitogen-activated protein kinases, inhibits proliferation, induces differentiation and suppresses the malignant phenotype of human colon carcinoma cells. Oncogene. 2003;22:2186-91 pubmed
    ..It is concluded that PAF is a modulator of proliferation and differentiation in human epithelial-derived colon carcinoma cells. ..
  22. 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. ..
  23. Xu L, Li L, Shu H. TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and induces apoptosis. J Biol Chem. 2004;279:17278-82 pubmed
    ..Our studies identified a novel TRAF family member that is involved in MEKK3 signaling and apoptosis. ..
  24. Han S, Roman J. COX-2 inhibitors suppress lung cancer cell growth by inducing p21 via COX-2 independent signals. Lung Cancer. 2006;51:283-96 pubmed
    ..These observations unveil a mechanism for p21 gene regulation by COX-2 inhibitors in lung carcinoma cell growth and this pathway represents a potential target for therapy. ..
  25. Chao T, Hayashi M, Tapping R, Kato Y, Lee J. MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway. J Biol Chem. 1999;274:36035-8 pubmed
    ..Taken together, these results identify MEKK3 as a kinase that regulates the activity of MEK5 and BMK1 during growth factor-induced cellular stimulation. ..
  26. 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. ..
  27. Suzuki H, Suda N, Shiga M, Kobayashi Y, Nakamura M, Iseki S, et al. Apert syndrome mutant FGFR2 and its soluble form reciprocally alter osteogenesis of primary calvarial osteoblasts. J Cell Physiol. 2012;227:3267-77 pubmed publisher
  28. 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. ..
  29. Garner A, Weston C, Todd D, Balmanno K, Cook S. Delta MEKK3:ER* activation induces a p38 alpha/beta 2-dependent cell cycle arrest at the G2 checkpoint. Oncogene. 2002;21:8089-104 pubmed
  30. Sun W, Ge N, Yu Y, Burlingame S, Li X, Zhang M, et al. Phosphorylation of Thr-516 and Ser-520 in the kinase activation loop of MEKK3 is required for lysophosphatidic acid-mediated optimal IkappaB kinase beta (IKKbeta)/nuclear factor-kappaB (NF-kappaB) activation. J Biol Chem. 2010;285:7911-8 pubmed publisher
    ..Furthermore, substitution of these two residues with alanine abolished the ability of MEKK3 to mediate lysophosphatidic acid-induced optimal IKKbeta/NF-kappaB activation. ..
  31. Lerner Marmarosh N, Yoshizumi M, Che W, Surapisitchat J, Kawakatsu H, Akaike M, et al. Inhibition of tumor necrosis factor-[alpha]-induced SHP-2 phosphatase activity by shear stress: a mechanism to reduce endothelial inflammation. Arterioscler Thromb Vasc Biol. 2003;23:1775-81 pubmed
    ..These results suggest that SHP-2 is a key mediator for the inhibitory effects of shear stress on TNF-alpha signaling in part via regulating MEKK3/Gab1 interaction, MEKK3 signaling, and subsequent adhesion molecule expression. ..
  32. Matitau A, Scheid M. Phosphorylation of MEKK3 at threonine 294 promotes 14-3-3 association to inhibit nuclear factor kappaB activation. J Biol Chem. 2008;283:13261-8 pubmed publisher
    ..Thus, this study identifies a potentially important regulatory step in MEKK3 signaling via dephosphorylation of Thr(294), which reduces 14-3-3 binding correlating with MEKK3 pathway activation. ..
  33. Di Y, Li S, Wang L, Zhang Y, Dorf M. Homeostatic interactions between MEKK3 and TAK1 involved in NF-kappaB signaling. Cell Signal. 2008;20:705-13 pubmed publisher
    ..The data provide insights into the homeostatic interactions that maintain basal NF-kappaB levels by holding the enzymes MEKK3 and TAK1 in their inactive state. ..
  34. Plun Favreau H, Klupsch K, Moisoi N, Gandhi S, Kjaer S, Frith D, et al. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nat Cell Biol. 2007;9:1243-52 pubmed
    ..We suggest that PINK1-dependent phosphorylation of HtrA2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress. ..
  35. Blonska M, Shambharkar P, Kobayashi M, Zhang D, Sakurai H, Su B, et al. TAK1 is recruited to the tumor necrosis factor-alpha (TNF-alpha) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-kappaB activation. J Biol Chem. 2005;280:43056-63 pubmed
    ..Together, we conclude that TAK1 is recruited to the TNF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-kappaB in TNF-alpha signaling. ..
  36. Samanta A, Huang H, Bast R, Liao W. Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappaB. J Biol Chem. 2004;279:7576-83 pubmed
    ..As such, MEKK3 may serve as a therapeutic target to control cancer cell resistance to cytokine- or drug-induced apoptosis. ..
  37. Callihan P, Ali M, Salazar H, Quach N, Wu X, Stice S, et al. Convergent regulation of neuronal differentiation and Erk and Akt kinases in human neural progenitor cells by lysophosphatidic acid, sphingosine 1-phosphate, and LIF: specific roles for the LPA1 receptor. ASN Neuro. 2014;6: pubmed publisher
    ..The pleiotropic effects of LPA may reflect differences in receptor subtype expression or cross talk with LIF receptor signaling. ..
  38. Adams D, Sachs N, Vaillancourt R. Phosphorylation of the stress-activated protein kinase, MEKK3, at serine 166. Arch Biochem Biophys. 2002;407:103-16 pubmed
    ..Nonetheless, these results suggest that MEKK3 is a convergence point of multiple upstream signaling pathways. ..
  39. Cooper B, Brimer N, Stoler M, Vande Pol S. Suprabasal overexpression of beta-1 integrin is induced by bovine papillomavirus type 1. Virology. 2006;355:102-14 pubmed publisher
    ..The ability of BPV-1 E7 to support beta1-integrin expression and EGF independent DNA synthesis and the activation of ERK are the first biochemical correlates of its expression in keratinocytes...
  40. He R, Sang H, Ye R. Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R. Blood. 2003;101:1572-81 pubmed
    ..The ability of FPRL1/LXA4R to mediate 2 drastically different and opposite functions suggests that it plays a role in the modulation of inflammatory and immune responses. ..
  41. Fan X, Subramaniam R, Weiss M, Monnier V. Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation. Arch Biochem Biophys. 2003;409:274-86 pubmed
    ..Our findings suggest that the presence of chronically elevated levels of MGO-modified bovine serum albumin may contribute to elevated levels of TNFalpha in diabetes. ..
  42. Yao J, Kim T, Qin J, Jiang Z, Qian Y, Xiao H, et al. Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFkappaB activation pathways bifurcate at IL-1 receptor-associated kinase modification. J Biol Chem. 2007;282:6075-89 pubmed
    ..These results provide significant insight to our further understanding of NFkappaB activation pathways. ..
  43. Nho C, O Dwyer P. NF-kappaB activation by the chemopreventive dithiolethione oltipraz is exerted through stimulation of MEKK3 signaling. J Biol Chem. 2004;279:26019-27 pubmed
    ..These results implicate a novel signaling pathway for the action of oltipraz in QR gene regulation. ..
  44. Yamasaki S, Sakata Sogawa K, Hasegawa A, Suzuki T, Kabu K, Sato E, et al. Zinc is a novel intracellular second messenger. J Cell Biol. 2007;177:637-45 pubmed
    ..Collectively, our findings indicate that zinc is a novel intracellular second messenger. ..
  45. Konno H, Yamamoto T, Yamazaki K, Gohda J, Akiyama T, Semba K, et al. TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNA. PLoS ONE. 2009;4:e5674 pubmed publisher
    ..Given its essential role in signaling by various receptors involved in the acquired immune system, TRAF6 represents a key molecule in innate and antigen-specific immune responses against viral infection. ..
  46. Lee T, Huang Q, Oikemus S, Shank J, Ventura J, Cusson N, et al. The death domain kinase RIP1 is essential for tumor necrosis factor alpha signaling to p38 mitogen-activated protein kinase. Mol Cell Biol. 2003;23:8377-85 pubmed
    ..Taken together, these studies suggest a mechanism whereby RIP1 may mediate the p38 MAP kinase response to TNF-alpha, by recruiting the MAP3K MEKK3. ..
  47. Shinohara H, Yamasaki S, Maeda S, Saito T, Kurosaki T. Regulation of NF-kappaB-dependent T cell activation and development by MEKK3. Int Immunol. 2009;21:393-401 pubmed publisher
    ..Furthermore, T cell-specific deletion of MEKK3 resulted in reduced numbers of thymocytes and peripheral T cells. Thus, our results provide genetic evidence that MEKK3 plays a crucial role in adaptive immunity. ..
  48. Champion A, Picaud A, Henry Y. Reassessing the MAP3K and MAP4K relationships. Trends Plant Sci. 2004;9:123-9 pubmed
  49. 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. ..
  50. Lee C, Onesime D, Reddy C, Dhanasekaran N, Reddy E. JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors. Proc Natl Acad Sci U S A. 2002;99:14189-94 pubmed
    ..Thus, JLP defines a family of scaffolding proteins that bring MAPKs and their target transcription factors together for the execution of specific signaling pathways. ..
  51. Fritz A, Brayer K, McCormick N, Adams D, Wadzinski B, Vaillancourt R. Phosphorylation of serine 526 is required for MEKK3 activity, and association with 14-3-3 blocks dephosphorylation. J Biol Chem. 2006;281:6236-45 pubmed
    ..In summary, Ser526 of MEKK3 is an autophosphorylation site within the T-loop that is regulated by PP2A and 14-3-3 proteins. ..
  52. Sokolova O, Maubach G, Naumann M. MEKK3 and TAK1 synergize to activate IKK complex in Helicobacter pylori infection. Biochim Biophys Acta. 2014;1843:715-24 pubmed publisher
    ..Overall, our data uncover H. pylori-induced interactions and protein modifications of the IKK complex, and its upstream regulatory factors involved in NF-?B activation. ..
  53. 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. ..