Gene Symbol: MEKK3
Description: mitogen-activated protein kinase kinase kinase 3
Alias: MAPKKK3, MEKK3, mitogen-activated protein kinase kinase kinase 3, MAP/ERK kinase kinase 3, MAPK/ERK kinase kinase 3, MEK kinase 3, MEKK 3
Species: human
Products:     MEKK3

Top Publications

  1. Choudhary S, Rosenblatt K, Fang L, Tian B, Wu Z, Brasier A. High throughput short interfering RNA (siRNA) screening of the human kinome identifies novel kinases controlling the canonical nuclear factor-κB (NF-κB) activation pathway. J Biol Chem. 2011;286:37187-95 pubmed publisher
    ..Six kinases were validated, including ATM, CDK2, -5, and -7, CALM3, MAPAKP5, and MAP3K/MEKK3. The surprising function of ATM in TNF signaling was confirmed where reduced NF-κB/RelA translocation and Ser-276 ..
  2. Bi G, Zhou Z, Wang W, Li L, Rao S, Wu Y, et al. Receptor-Like Cytoplasmic Kinases Directly Link Diverse Pattern Recognition Receptors to the Activation of Mitogen-Activated Protein Kinase Cascades in Arabidopsis. Plant Cell. 2018;30:1543-1561 pubmed publisher
    ..Here, we show that two highly related MAPKKKs, MAPKKK3 and MAPKKK5, mediate MPK3/6 activation by at least four PRRs and confer resistance to bacterial and fungal ..
  3. Ahmad S, St Hilaire V, Dandepally S, Johnson G, Williams A, Scott J. Discovery and characterization of an iminocoumarin scaffold as an inhibitor of MEKK2 (MAP3K2). Biochem Biophys Res Commun. 2018;496:205-211 pubmed publisher
    ..Analog Compound 1s (16 nM IC50) was further verified by external testing to inhibit MEKK2 and MEKK3 with similar potencies...
  4. Sandoval L, Jiang H, Wang D. The Dietary Restriction-Like Gene drl-1, Which Encodes a Putative Serine/Threonine Kinase, Is Essential for Orsay Virus Infection in Caenorhabditis elegans. J Virol. 2019;93: pubmed publisher
    ..the dietary restriction-like (drl-1) gene, which encodes a serine/threonine kinase similar to the mammalian MEKK3 kinase...
  5. Panagopoulos I, Gorunova L, Davidson B, Heim S. Novel TNS3-MAP3K3 and ZFPM2-ELF5 fusion genes identified by RNA sequencing in multicystic mesothelioma with t(7;17)(p12;q23) and t(8;11)(q23;p13). Cancer Lett. 2015;357:502-9 pubmed publisher
  6. Li G, Domenico J, Jia Y, Lucas J, Gelfand E. NF-kappaB-dependent induction of cathelicidin-related antimicrobial peptide in murine mast cells by lipopolysaccharide. Int Arch Allergy Immunol. 2009;150:122-32 pubmed publisher
    ..MEKK2 or MEKK3 were overexpressed by transfection...
  7. Ma L, Zhao W, Zhu F, Yuan F, Xie N, Li T, et al. Global Characteristics of CSIG-Associated Gene Expression Changes in Human HEK293 Cells and the Implications for CSIG Regulating Cell Proliferation and Senescence. Front Endocrinol (Lausanne). 2015;6:69 pubmed publisher
  8. Zhou Z, Rawnsley D, Goddard L, Pan W, Cao X, Jakus Z, et al. The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3 signaling and KLF expression. Dev Cell. 2015;32:168-80 pubmed publisher
    ..These changes in gene expression result from increased activity of MEKK3, a mitogen-activated protein kinase that binds CCM2 in endothelial cells...
  9. Ho M, Liang C, Liang S. MIG-7 and phosphorylated prohibitin coordinately regulate lung cancer invasion/metastasis. Oncotarget. 2015;6:381-93 pubmed
    ..Association of phospho-PHBT258 with MEKK1 but not MEKK3 activates IKK/IκB/NF-κB and MEK/ERK to increase cellular COX-2/PGE2 and an E-cadherin suppressor Snail ..

More Information


  1. Shang H, Chang J, Lin J, Lin J, Hsu S, Liu C, et al. Deguelin inhibits the migration and invasion of U-2 OS human osteosarcoma cells via the inhibition of matrix metalloproteinase-2/-9 in vitro. Molecules. 2014;19:16588-608 pubmed publisher
    ..proliferation and cell growth-associated protein levels, such as SOS1, PKC, Ras, PI3K, p-AKT(Ser473), IRE-1α, MEKK3, iNOS, COX2, p-ERK1/2, p-JNK1/2, p-p38; the cell motility and focal adhesion-associated protein levels, such as ..
  2. Umapathy G, El Wakil A, Witek B, Chesler L, Danielson L, Deng X, et al. The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma. Sci Signal. 2014;7:ra102 pubmed publisher activated by ALK through a pathway mediated by phosphoinositide 3-kinase (PI3K), AKT, MAPK kinase kinase 3 (MEKK3), and MAPK kinase 5 (MEK5). ALK-induced transcription of MYCN and stimulation of cell proliferation required ERK5...
  3. Sun T, Nitta Y, Zhang Q, Wu D, Tian H, Lee J, et al. Antagonistic interactions between two MAP kinase cascades in plant development and immune signaling. EMBO Rep. 2018;19: pubmed publisher
    ..Here, we report that MAPKKK3/MAPKKK5 form a kinase cascade with MKK4/MKK5 and MPK3/MPK6 to transduce defense signals downstream of multiple ..
  4. Uhlik M, Abell A, Johnson N, Sun W, Cuevas B, Lobel Rice K, et al. Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nat Cell Biol. 2003;5:1104-10 pubmed
    ..We have discovered a novel scaffold protein that binds to actin, the GTPase Rac, and the upstream kinases MEKK3 and MKK3 in the p38 MAPK phospho-relay module...
  5. Chen T, Chen C, Wen H, Chang C, Wang H, Chuu C, et al. YAP promotes myogenic differentiation via the MEK5-ERK5 pathway. FASEB J. 2017;31:2963-2972 pubmed publisher
    ..Specific interactions between YAP and proteins in the ERK5 pathway, such as MEK kinase 3 (MEKK3) and ERK5, were illustrated by coimmunoprecipitation experiments...
  6. Chu W, Guan L, Huang D, Ren Y, Zhou Y. Lovastatin exerts protective effects on endothelial cells via upregulation of PTK2B. Exp Ther Med. 2016;12:1741-1749 pubmed
    ..In conclusion, the results of the present study suggested that lovastatin protects against ox-LDL-induced cell injury, potentially via the upregulation of PTK2B, which regulates the anti-apoptosis signaling pathway. ..
  7. Wilkinson E, Sidaway J, Cross M. Statin regulated ERK5 stimulates tight junction formation and reduces permeability in human cardiac endothelial cells. J Cell Physiol. 2018;233:186-200 pubmed publisher
    The MEKK3/MEK5/ERK5 signaling axis is required for cardiovascular development in vivo...
  8. Wu L, Chen X, Zhao J, Martin B, Zepp J, Ko J, et al. A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis. J Exp Med. 2015;212:1571-87 pubmed publisher
    ..Here we report a novel IL-17-mediated cascade via the IL-17R-Act1-TRAF4-MEKK3-ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation...
  9. Forde B, Cutler S, Zaman N, Krysan P. Glutamate signalling via a MEKK1 kinase-dependent pathway induces changes in Arabidopsis root architecture. Plant J. 2013;75:1-10 pubmed publisher
    ..This led to the discovery that root growth in a triple mekk1 mekk2 mekk3 mutant (mekk1/2/3), defective in a set of three tandemly arranged MAP3Ks, was almost insensitive to l-Glu...
  10. Choi J, Foley M, Zhou Z, Wong W, Gokoolparsadh N, Arthur J, et al. Micro-CT Imaging Reveals Mekk3 Heterozygosity Prevents Cerebral Cavernous Malformations in Ccm2-Deficient Mice. PLoS ONE. 2016;11:e0160833 pubmed publisher
    ..This quantitative approach also demonstrated a rescue of CCM lesions with simultaneous deletion of one allele of Mekk3. This method would enhance the value of the established mouse models to study the molecular basis and potential ..
  11. Li S, Pinard M, Wang Y, Yang L, Lin R, Hiscott J, et al. Crosstalk between the TNF and IGF pathways enhances NF-κB activation and signaling in cancer cells. Growth Horm IGF Res. 2015;25:253-61 pubmed publisher
    ..This effect was AKT-dependent and mediated via mitogen-activated protein kinase kinase kinase 3(MEKK3) activation...
  12. Li K, Wang M, Hu Y, Xu N, Yu Q, Wang Q. TAK1 knockdown enhances lipopolysaccharide-induced secretion of proinflammatory cytokines in myeloid cells via unleashing MEKK3 activity. Cell Immunol. 2016;310:193-198 pubmed publisher
    ..TAK1 negatively regulates mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3). Moreover, TAK1 inhibited MEKK3 activation, which, in turn, activated NF-?B...
  13. Fisher O, Deng H, Liu D, Zhang Y, Wei R, Deng Y, et al. Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex. Nat Commun. 2015;6:7937 pubmed publisher
    ..The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this ..
  14. Santoro R, Zanotto M, Carbone C, Piro G, Tortora G, Melisi D. MEKK3 Sustains EMT and Stemness in Pancreatic Cancer by Regulating YAP and TAZ Transcriptional Activity. Anticancer Res. 2018;38:1937-1946 pubmed
    Pancreatic cancer is one of the most threatening and poorly understood human malignancies. MEKK3 (MAP3K3) is a serine/threonine kinase activated by different signaling pathways...
  15. Bai J, Jie H, Wei S, Wang S, Guo H, Tang Q. GART mediates the renewal of intestinal epithelial barrier via p38/p53/PUMA cascade in colitis. Apoptosis. 2016;21:1386-1397 pubmed
    ..inhibition of GART induced cellular apoptosis and suppressed the migration of IECs through the activation of the MEKK3-MKK3-p38 mitogen-activated protein kinase (MAPK) pathway, following with the dys-regulation of p53 and p53 up-..
  16. Tang A, Choi J, Kotzin J, Yang Y, Hong C, Hobson N, et al. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017;545:305-310 pubmed publisher
    ..CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be ..
  17. Lu J, Liu L, Zheng M, Li X, Wu A, Wu Q, et al. MEKK2 and MEKK3 suppress Hedgehog pathway-dependent medulloblastoma by inhibiting GLI1 function. Oncogene. 2018;37:3864-3878 pubmed publisher
    ..Here we show that MEKK2 (MAP3K2) and MEKK3 (MAP3K3) inhibit GLI1 transcriptional activity and oncogenic function through phosphorylation on multiple Ser/Thr ..
  18. Cuttano R, Rudini N, Bravi L, Corada M, Giampietro C, Papa E, et al. KLF4 is a key determinant in the development and progression of cerebral cavernous malformations. EMBO Mol Med. 2016;8:6-24 pubmed publisher
    ..Here, we report that Ccm1 ablation leads to the activation of a MEKK3-MEK5-ERK5-MEF2 signaling axis that induces a strong increase in Kruppel-like factor 4 (KLF4) in ECs in vivo...
  19. Sugiyama H, Takahashi K, Yamamoto T, Iwasaki M, Narita M, Nakamura M, et al. Nat1 promotes translation of specific proteins that induce differentiation of mouse embryonic stem cells. Proc Natl Acad Sci U S A. 2017;114:340-345 pubmed publisher
    ..These data collectively show that Nat1 is involved in the translation of proteins that are required for cell differentiation. ..
  20. Neoh C, Wu W, Dai G, Su J, Liu C, Su T, et al. Flaccidoxide-13-Acetate Extracted from the Soft Coral Cladiella kashmani Reduces Human Bladder Cancer Cell Migration and Invasion through Reducing Activation of the FAK/PI3K/AKT/mTOR Signaling Pathway. Molecules. 2017;23: pubmed publisher
    ..A), Ras, mitogen-activated protein kinase kinase 7 (MKK7) and mitogen-activated protein kinase kinase kinase 3 (MEKK3), and increased the expressions of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 in RT4 and T24 ..
  21. Sylvain Prévost S, Ear T, Simard F, Fortin C, Dubois C, Flamand N, et al. Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses. J Immunol. 2015;195:5393-403 pubmed publisher
    ..Inhibition of TAK1 also impaired MEKK3 (but not MEKK1) activation by fMLF...
  22. Cullere X, Plovie E, Bennett P, Macrae C, Mayadas T. The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3. Proc Natl Acad Sci U S A. 2015;112:14284-9 pubmed publisher
    ..In vitro, both CCM2L and CCM2 bind MEKK3 in a complex with CCM1...
  23. Yao L, Ye Y, Mao H, Lu F, He X, Lu G, et al. MicroRNA-124 regulates the expression of MEKK3 in the inflammatory pathogenesis of Parkinson's disease. J Neuroinflammation. 2018;15:13 pubmed publisher exposure to LPS, and the expression levels of miR-124, mitogen-activated protein kinase kinase kinase 3 (MEKK3), and the nuclear factor of kappaB (NF-κB) p-p65 were analysed...
  24. Chen Q, Lu H, Gan M, Chen L, He K, Fan G, et al. Expression and prognostic role of MEKK3 and pERK in patients with renal clear cell carcinoma. Asian Pac J Cancer Prev. 2015;16:2495-9 pubmed
    Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3) is an important serine/threonine protein kinase and a member of the MAPK family...
  25. Sun W, Zhao X, Yu Y, Fan Y, Wang H, Wang X, et al. Protein phosphatase 2A acts as a mitogen-activated protein kinase kinase kinase 3 (MEKK3) phosphatase to inhibit lysophosphatidic acid-induced IkappaB kinase beta/nuclear factor-kappaB activation. J Biol Chem. 2010;285:21341-8 pubmed publisher
    b>MEKK3 is a central intermediate signaling component in lysophosphatidic acid (LPA)-induced activation of the nuclear factor-kappaB (NF-kappaB)...
  26. Kriegs M, Kasten Pisula U, Rieckmann T, Holst K, Saker J, Dahm Daphi J, et al. The epidermal growth factor receptor modulates DNA double-strand break repair by regulating non-homologous end-joining. DNA Repair (Amst). 2010;9:889-97 pubmed publisher
    ..This regulation of NHEJ by EGFR was only blocked when ERK was affected by siRNA but not when AKT was knocked down. These data indicate that EGFR modulates DSB repair by regulating NHEJ via MAPK signalling. ..
  27. Carty C, Johnson N, Hutter C, Reiner A, Peters U, Tang H, et al. Genome-wide association study of body height in African Americans: the Women's Health Initiative SNP Health Association Resource (SHARe). Hum Mol Genet. 2012;21:711-20 pubmed publisher
    ..Specifically, we identify new loci that may reflect population-specific regulation of height and report several known height loci that are important in determining height in African-descent populations. ..
  28. 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
    ..In the present study, we found that Hsp90 interacted with MEKK3 in HEK293 cells...
  29. 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
    ..Although mitogen-activated protein kinase/extracellular-regulated kinase kinase kinase-3 (MEKK3) has been shown to participate in the activation of NFkappaB, its relations to apoptosis and cancer are unclear...
  30. Sun W, Kesavan K, Schaefer B, Garrington T, Ware M, Johnson N, et al. MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway. J Biol Chem. 2001;276:5093-100 pubmed
    MEKK2 and MEKK3 are two closely related mitogen-activated protein kinase (MAPK) kinase kinases. The kinase domains of MEKK2 and MEKK3 are nearly identical, although their N-terminal regulatory domains are significantly divergent...
  31. 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
    ..To address this question, we have expressed recombinant (His)6FLAG.MEKK3 in Sf9 insect cells and tethered the purified protein to Ni-Sepharose so that we could precipitate interacting ..
  32. Wang X, Hou Y, Deng K, Zhang Y, Wang D, Ding J. Structural Insights into the Molecular Recognition between Cerebral Cavernous Malformation 2 and Mitogen-Activated Protein Kinase Kinase Kinase 3. Structure. 2015;23:1087-96 pubmed publisher
    ..By interacting with the mitogen-activated protein kinase MEKK3, CCM2 either mediates the activation of MEKK3 signaling in response to osmotic stress or negatively regulates ..
  33. 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
    ..Interestingly, we also find that TAK1 and MEKK3 form a functional complex, in which TAK1 regulates autophosphorylation of MEKK3...
  34. 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
    ..We determined that active MEKK3 was capable of activating calcineurin/nuclear factor of activated T-cells (NFAT) signaling in cardiac myocytes and ..
  35. 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
    ..along with JNK (c-Jun NH2-terminal kinase) and p38MAPK, as well as their upstream kinases MKK4 (MAPK kinase 4) and MEKK3 (MAPK kinase kinase 3)...
  36. Jia W, Dong Y, Tao L, Pang L, Ren Y, Liang W, et al. MAP3K3 overexpression is associated with poor survival in ovarian carcinoma. Hum Pathol. 2016;50:162-9 pubmed publisher
    ..All these findings suggested that MAP3K3 overexpression is an independent poor prognostic indicator of OC and can be a clinically effective biomarker of OC. ..
  37. Takeda A, Oberoi Khanuja T, Glatz G, Schulenburg K, Scholz R, Carpy A, et al. Ubiquitin-dependent regulation of MEKK2/3-MEK5-ERK5 signaling module by XIAP and cIAP1. EMBO J. 2014;33:1784-801 pubmed publisher
    ..XIAP and cIAP1 conjugate predominantly K63-linked ubiquitin chains to MEKK2 and MEKK3 which directly impede MEK5-ERK5 interaction in a trimeric complex leading to ERK5 inactivation...
  38. Blonska M, You Y, Geleziunas R, Lin X. Restoration of NF-kappaB activation by tumor necrosis factor alpha receptor complex-targeted MEKK3 in receptor-interacting protein-deficient cells. Mol Cell Biol. 2004;24:10757-65 pubmed
    ..In this study, we reconstituted RIP-deficient Jurkat T cells with a fusion protein composed of full-length MEKK3 and the death domain of RIP (MEKK3-DD)...
  39. Lu H, Cao X, Chen Q, Chen L, Chen L, Gan M. The expression and role of MEKK3 in renal clear cell carcinoma. Anat Rec (Hoboken). 2015;298:727-34 pubmed publisher
    ..the relationship between Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3(MEKK3) and cell apoptosis, clinicopathology, and prognosis, we characterize the expression of MEKK3, survivin and stat3 ..
  40. 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
    ..TRAF7 also contains seven WD40 repeats at its C terminus. TRAF7 specifically interacted with MEKK3 and potentiated MEKK3-mediated AP1 and CHOP activation...
  41. Yang J, Lin Y, Guo Z, Cheng J, Huang J, Deng L, et al. The essential role of MEKK3 in TNF-induced NF-kappaB activation. Nat Immunol. 2001;2:620-4 pubmed
    ..Using mitogen-activated protein kinase kinase kinase 3 (MEKK3)-deficient fibroblast cells, we found that MEKK3 plays a critical role in TNF-induced NF-kappaB activation...
  42. Pratsinis H, Constantinou V, Pavlakis K, Sapkas G, Kletsas D. Exogenous and autocrine growth factors stimulate human intervertebral disc cell proliferation via the ERK and Akt pathways. J Orthop Res. 2012;30:958-64 pubmed publisher
  43. Erdogan E, Lamark T, Stallings Mann M, Lee Jamieson -, Pellecchia M, Pellechia M, et al. Aurothiomalate inhibits transformed growth by targeting the PB1 domain of protein kinase Ciota. J Biol Chem. 2006;281:28450-9 pubmed
    ..ATM has no appreciable inhibitory effect on other PB1-PB1 domain interactions, including p62-p62, p62-NBR1, and MEKK3-MEK5 interactions. ATM can form thio-gold adducts with cysteine residues on target proteins...
  44. 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
    MAPK/ERK kinase kinase 3 (MEKK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that functions upstream of the MAP kinases and IkappaB kinase...
  45. Cao X, Lu H, Zhang L, Chen L, Gan M. MEKK3 and survivin expression in cervical cancer: association with clinicopathological factors and prognosis. Asian Pac J Cancer Prev. 2014;15:5271-6 pubmed
    Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3) is an important protein kinase and a member of the MAPK family, which regulates cellular responses to environmental stress and serves as key ..
  46. Li Y, Li M, Min W, Han G, Wang L, Chen C, et al. Integrated in silico-in vitro characterization, identification and disruption of the intermolecular interaction between SH3 domain-containing protein kinases and human pituitary tumor-transforming gene 1. Gen Physiol Biophys. 2017;36:91-98 pubmed publisher
    ..All these suggest that the MAP3K M1P site is a potential interacting partner of MAP3K SH3 domain, which may mediate the intermolecular recognition between hPTTG1 and MAP3K. ..
  47. Lamark T, Perander M, Outzen H, Kristiansen K, Øvervatn A, Michaelsen E, et al. Interaction codes within the family of mammalian Phox and Bem1p domain-containing proteins. J Biol Chem. 2003;278:34568-81 pubmed
    ..lambda/iota- and zeta PKC; members of mitogen-activated protein kinase (MAPK) modules like MEK5, MEKK2, and MEKK3; and in several scaffold proteins involved in cellular signaling...
  48. Couto J, Vivero M, Kozakewich H, Taghinia A, Mulliken J, Warman M, et al. A somatic MAP3K3 mutation is associated with verrucous venous malformation. Am J Hum Genet. 2015;96:480-6 pubmed publisher
    ..Studies using global and conditional Map3k3 knockout mice have previously implicated MAP3K3 in vascular development. MAP3K3 dysfunction probably causes VVM in humans. ..
  49. Gilmore P, McCabe N, Quinn J, Kennedy R, Gorski J, Andrews H, et al. BRCA1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3. Cancer Res. 2004;64:4148-54 pubmed
    ..We identified mitogen-activated protein kinase (MAPK) kinase kinase 3 (MEKK3), an upstream regulator of the c-Jun NH(2)-terminal kinase/stress-activated protein kinase and p38/MAPK pathways, ..
  50. Channavajhala P, Rao V, Spaulding V, Lin L, Zhang Y. hKSR-2 inhibits MEKK3-activated MAP kinase and NF-kappaB pathways in inflammation. Biochem Biophys Res Commun. 2005;334:1214-8 pubmed
    Kinase suppressor of ras (KSR) and MEKK3 (MAP kinase kinase kinase) are integral members of the MAP kinase pathway...
  51. 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
    ..Here we show that MAPK-ERK kinase kinase (MEKK3) is an essential signal transducer of the MyD88-IRAK-TRAF6 complex in IL-1R-TLR4 signaling...
  52. Deacon K, Blank J. Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. J Biol Chem. 1997;272:14489-96 pubmed
    ..mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) kinase kinases, designated MEKK2 and MEKK3 (Blank, J.L., Gerwins, P., Elliott, E.M., Sather, S. and Johnson, G.L. (1996) J. Biol. Chem. 271, 5361-5368)...
  53. 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 disrupted Map3k3 (also known as Mekk3), which encodes Mekk3, a member of the Mekk/Ste11 family, in mice...
  54. Schwab C, Bozak C, Whitehouse N, Olson V. Amino acid limitation and flow to the duodenum at four stages of lactation. 2. Extent of lysine limitation. J Dairy Sci. 1992;75:3503-18 pubmed
    ..8% at the four respective stages of lactation. Extent of Lys limitation determined from responses in content and yield of milk protein approximated 25, 20, and 10 g/d during peak, early, and midlactation.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  55. 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
    ..rear end acidic cluster region of the p62 PB1 domain binds the front end basic region of the MAPK kinase kinase, MEKK3. p62 and MEKK3 co-localize in speckles or aggregates that are centers for organizing TRAF6-regulated NF-kappaB ..
  56. Qin J, Yao J, Cui G, Xiao H, Kim T, Fraczek J, et al. TLR8-mediated NF-kappaB and JNK activation are TAK1-independent and MEKK3-dependent. J Biol Chem. 2006;281:21013-21 pubmed
    ..other hand, TLR8-mediated IkappaBalpha phosphorylation, NF-kappaB, and JNK activation are completely abolished in MEKK3(-/-) MEFs, whereas IL-1-mediated signaling was only moderately reduced in these deficient MEFs as compared with ..
  57. He Y, Wang L, Liu W, Zhong J, Bai S, Wang Z, et al. MAP3K3 expression in tumor cells and tumor-infiltrating lymphocytes is correlated with favorable patient survival in lung cancer. Sci Rep. 2015;5:11471 pubmed publisher
    ..MAP3K3 may potentially not only serve as diagnostic/prognostic markers for patients with lung cancer but also provide an indicator for future investigations into immunomodulatory therapies for lung cancer. ..
  58. 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
    The protein kinase MEKK3 is essential for tumor necrosis factor alpha (TNFalpha)- and lipopolysaccharide-induced activation of nuclear factor kappaB, although the mechanism by which TNF receptor 1 and Toll-like receptors regulate MEKK3 ..
  59. Viana N, Reis S, Dip N, Morais D, Moura C, Silva I, et al. MicroRNAs 143 and 145 may be involved in benign prostatic hyperplasia pathogenesis through regulation of target genes and proteins. Int J Biol Markers. 2014;29:e246-52 pubmed publisher
    ..The aim of this study was to analyze the roles of miR-143 and miR-145, as well as the gene and protein expression of their targets (KRAS, ERK5, MAP3K3, and MAP4K4) in the pathogenesis of benign prostatic hyperplasia (BPH)...
  60. 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
    ..Through utilization of a yeast two-hybrid screen, we have identified MEKK3 as a molecule that physically interacts with MEK5...
  61. 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
    ..constructs of NIK and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3). We found that both MEKK3 and NIK exert effects on IKKalpha/beta activation, but through different pathways...
  62. Crose L, Hilder T, Sciaky N, Johnson G. Cerebral cavernous malformation 2 protein promotes smad ubiquitin regulatory factor 1-mediated RhoA degradation in endothelial cells. J Biol Chem. 2009;284:13301-5 pubmed publisher
  63. 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
    ..evidence for an intimate mutual control of the IKK complex by mitogen-activated protein kinase kinase kinase 3 (MEKK3) and transforming growth factor ? activated kinase 1 (TAK1)...
  64. Che W, Lerner Marmarosh N, Huang Q, Osawa M, Ohta S, Yoshizumi M, et al. Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression. Circ Res. 2002;90:1222-30 pubmed
    ..Interestingly, Gab1 inhibited c-Jun transcriptional activity induced by MEKK3 but not MEKK1 and MEK4...
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    ..Expression of dominant negative mutants of MEKK2 and MEKK3 also blocked activation of ERK5 by WNK1...
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    ..We now show that MEKK2 and MEKK3 can in vivo activate IKK-alpha and IKK-beta, induce site-specific IkappaBalpha phosphorylation, and, relatively ..
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    ..we demonstrate that an interaction between the PB1 domains of NBR1 and the mitogen-activated kinase kinase 3 (MEKK3) enables the formation of a signaling complex required for the activation of JNK...
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    ..isoforms were isolated in a two-hybrid screen for proteins interacting with the N-terminal regulatory domain of MEKK3. 14-3-3 proteins bound both the N-terminal regulatory and C-terminal kinase domains of MEKK3...
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    ..In this study, we show that T cell conditional ablation of MEKK3, a Ser/Thr kinase in the MAPK cascade, causes a significant reduction in peripheral T cell numbers in the ..
  71. 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
    b>MEKK3 serves as a critical intermediate signaling molecule in lysophosphatidic acid-mediated nuclear factor-kappaB (NF-kappaB) activation...
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    ..growth factor-beta-activated kinase 1 (TAK1) and mitogen-activated protein kinase (MAPK) kinase kinase 3 (MEKK3) are both crucial for IL-1-dependent activation of NF-kappaB, their potential functional and physical interactions ..
  73. 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. ..
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    ..CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during ..
  75. Hasan R, Sharma R, Saraya A, Chattopadhyay T, Dattagupta S, Walfish P, et al. Mitogen activated protein kinase kinase kinase 3 (MAP3K3/MEKK3) overexpression is an early event in esophageal tumorigenesis and is a predictor of poor disease prognosis. BMC Cancer. 2014;14:2 pubmed publisher
    Mitogen-activated protein kinase kinase kinase3 (MAP3K3/MEKK3) was identified to be differentially expressed in esophageal squamous cell carcinoma (ESCC) using cDNA microarrays by our laboratory...
  76. Fontenele E, Moraes M, D Alva C, Pinheiro D, Landim S, Barros F, et al. Association Study of GWAS-Derived Loci with Height in Brazilian Children: Importance of MAP3K3, MMP24 and IGF1R Polymorphisms for Height Variation. Horm Res Paediatr. 2015;84:248-53 pubmed publisher
    ..Polymorphisms in MAP3K3, MMP24 and IGF1R act additively on height in children of an admixed population. These results demonstrate the importance of these loci for children's height. ..
  77. Linares J, Duran A, Reina Campos M, Aza Blanc P, Campos A, Moscat J, et al. Amino Acid Activation of mTORC1 by a PB1-Domain-Driven Kinase Complex Cascade. Cell Rep. 2015;12:1339-52 pubmed publisher
    ..p62 is phosphorylated via a cascade that includes MEK3/6 and p38δ and is driven by the PB1-containing kinase MEKK3. This phosphorylation results in the recruitment of TRAF6 to p62, the ubiquitination and activation of mTOR, and ..
  78. 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
    MEKK2 and MEKK3 are MAPK kinase kinases that activate the ERK5 pathway by phosphorylating and activating the MAPK kinase, MEK5. Activated MEK5 then phosphorylates and activates ERK5...
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    b>MEKK3 is a mitogen-activated protein kinase kinase kinase that participates in various signaling pathways. One of its functions is to activate the ERK5 signal pathway by phosphorylating and activating MEK5...
  80. 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
    ..mutants, we uncovered two parallel IL-1-mediated signaling pathways for NFkappaB activation, TAK1-dependent and MEKK3-dependent, respectively. These two pathways bifurcate at the level of IRAK modification...
  81. Ellinger Ziegelbauer H, Brown K, Kelly K, Siebenlist U. Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative. J Biol Chem. 1997;272:2668-74 pubmed
    ..We have isolated a cDNA encoding human MEKK3. Transfected MEKK3 has the ability to activate both SAPK and ERK pathways, but does not induce p38 activity, in ..