MKK3

Summary

Gene Symbol: MKK3
Description: mitogen-activated protein kinase kinase 3
Alias: MAPKK3, MEK3, MKK3, PRKMK3, SAPKK-2, SAPKK2, dual specificity mitogen-activated protein kinase kinase 3, MAP kinase kinase 3, MAPK/ERK kinase 3, MAPKK 3, MEK 3, SAPK kinase 2, stress-activated protein kinase kinase 2
Species: human
Products:     MKK3

Top Publications

  1. Derijard B, Raingeaud J, Barrett T, Wu I, Han J, Ulevitch R, et al. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995;267:682-5 pubmed
    ..Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase...
  2. Han J, Wang X, Jiang Y, Ulevitch R, Lin S. Identification and characterization of a predominant isoform of human MKK3. FEBS Lett. 1997;403:19-22 pubmed
    We have obtained a novel cDNA species of MKK3, termed MKK3b. MKK3b cDNA differs from its original form, MKK3, at the 5'-end, encoding 29 extra amino acids in the N-terminus...
  3. Han Q, Leng J, Bian D, Mahanivong C, Carpenter K, Pan Z, et al. Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. J Biol Chem. 2002;277:48379-85 pubmed
    ..Using constitutively active MAPK kinases, we found that both constitutively active MKK3 and MKK6 mutants were able to activate p38 MAPK and up-regulate uPA expression, but only dominant negative MKK3 ..
  4. Demuth T, Reavie L, Rennert J, Nakada M, Nakada S, Hoelzinger D, et al. MAP-ing glioma invasion: mitogen-activated protein kinase kinase 3 and p38 drive glioma invasion and progression and predict patient survival. Mol Cancer Ther. 2007;6:1212-22 pubmed
    ..We identify mitogen-activated protein kinase (MAPK) kinase 3 (MKK3) as a key activator of p38 MAPK in glioma; MKK3 activation is strongly correlated with p38 activation in vitro and ..
  5. Jia M, Souchelnytskyi N, Hellman U, O Hare M, Jat P, Souchelnytskyi S. Proteome profiling of immortalization-to-senescence transition of human breast epithelial cells identified MAP2K3 as a senescence-promoting protein which is downregulated in human breast cancer. Proteomics Clin Appl. 2010;4:816-28 pubmed publisher
    ..we described a proteome profile of the immortalization-to-senescence transition for human breast epithelial cells, and identified MAP2K3 as a protein that promotes senescence in these cells. ..
  6. Tsai C, Cheng Y, Lu D, Wang S, Chang C, Chang P, et al. Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers. Toxicol Appl Pharmacol. 2018;338:182-190 pubmed publisher
    ..Furthermore, inhibition of ER by fulvestrant and tamoxifen phosphorylated p38 MAPK, and inhibition of Rac, MKK3/6, and p38 reversed fulvestrant-reduced Cx43 expression...
  7. Han A, Lim T, Song Y, Jang M, Rhee Y, Hong H, et al. Inhibitory Effect of Opuntia humifusa Fruit Water Extract on Solar Ultraviolet-Induced MMP-1 Expression. Int J Mol Sci. 2018;19: pubmed publisher
    ..As upstream signaling pathways for AP-1, MKK4-JNK, MEK-ERK, and MKK3/6-p38 phosphorylation were downregulated by OHE treatment...
  8. Swaroop S, Sengupta N, Suryawanshi A, Adlakha Y, Basu A. HSP60 plays a regulatory role in IL-1β-induced microglial inflammation via TLR4-p38 MAPK axis. J Neuroinflammation. 2016;13:27 pubmed publisher
    ..Furthermore, silencing of upstream modulator of p38, i.e., MEK3/6 also reduced HSP60-induced inflammation...
  9. Biesemann N, Mendler L, Kostin S, Wietelmann A, Borchardt T, Braun T. Myostatin induces interstitial fibrosis in the heart via TAK1 and p38. Cell Tissue Res. 2015;361:779-87 pubmed publisher
    ..Increased expression of myostatin in heart muscle cells caused interstitial fibrosis via activation of the TAK-1-MKK3/6-p38 signaling pathway, compromising cardiac function in older mice...

More Information

Publications161 found, 100 shown here

  1. Singh R. Model Predicts That MKP1 and TAB1 Regulate p38? Nuclear Pulse and Its Basal Activity through Positive and Negative Feedback Loops in Response to IL-1. PLoS ONE. 2016;11:e0157572 pubmed publisher
    ..Our model provides insight into the mechanism of p38? activation, reason for its transient nuclear response, and explanation of the basal activity of MKK3/6 and p38?, which has been experimentally observed by other groups.
  2. Srivastava A, Shinn A, Lee P, Mannam P. MKK3 mediates inflammatory response through modulation of mitochondrial function. Free Radic Biol Med. 2015;83:139-48 pubmed publisher
    Mitochondria are increasingly recognized as drivers of inflammatory responses. MAP kinase kinase 3 (MKK3), a dual-specificity protein kinase, is activated in inflammation and in turn activates p38 MAP kinase signaling...
  3. Wang L, Chen C, Feng S, Lei P, Tian J. Mitogen-activated protein kinase kinase 3 induces cell cycle arrest via p38 activation mediated Bmi-1 downregulation in hepatocellular carcinoma. Mol Med Rep. 2016;13:243-8 pubmed publisher
    ..Mitogen-activated protein kinase kinase 3 (MKK3), has been reported as a novel tumor suppressor in breast cancer...
  4. McLaughlin N, Banerjee A, Kelher M, Gamboni Robertson F, Hamiel C, Sheppard F, et al. Platelet-activating factor-induced clathrin-mediated endocytosis requires beta-arrestin-1 recruitment and activation of the p38 MAPK signalosome at the plasma membrane for actin bundle formation. J Immunol. 2006;176:7039-50 pubmed
    ..clathrin, 3) recruitment and activation of the apoptosis signal-regulating kinase-1/MAPK kinase-3/p38 MAPK (ASK1/MKK3/p38 MAPK) signalosome, 4) cell polarization, and 5) distinct actin bundle formation at the PAFR...
  5. Hussey S, Lum H, Alvarez A, Cipriani Y, Garduño Garcia J, Anaya L, et al. A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle. Diabetologia. 2014;57:582-91 pubmed publisher
    ..The activation of this pathway by NEFA may be involved in the pathogenesis of insulin resistance in humans. ClinicalTrials.gov NCT01740817. ..
  6. Senger K, Pham V, Varfolomeev E, Hackney J, Corzo C, Collier J, et al. The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation. Sci Signal. 2017;10: pubmed publisher
    ..Biochemical analyses identified the MAPK kinases MEK3 and MEK6 and the MAPKs p38? and p38? as downstream effectors of TPL2 in these cells...
  7. Hutter D, Chen P, Barnes J, Liu Y. Catalytic activation of mitogen-activated protein (MAP) kinase phosphatase-1 by binding to p38 MAP kinase: critical role of the p38 C-terminal domain in its negative regulation. Biochem J. 2000;352 Pt 1:155-63 pubmed
  8. Bak M, Hong S, Lee J, Jeong W. Red ginseng marc oil inhibits iNOS and COX-2 via NFκB and p38 pathways in LPS-stimulated RAW 264.7 macrophages. Molecules. 2012;17:13769-86 pubmed publisher
    ..of p38 mitogen-activated protein kinase (MAPK) and its upstream kinases including MAPK kinases 3/6 (MKK3/6) and TAK 1 (TGF-β activated kinase 1)...
  9. Cheng Y, Zhu Y, Xu W, Xu J, Yang M, Chen P, et al. PKCα in colon cancer cells promotes M1 macrophage polarization via MKK3/6-P38 MAPK pathway. Mol Carcinog. 2018;57:1017-1029 pubmed publisher
    ..Mechanistically, PKCα targeted P38 via MKK3/6 to promote IL12 and GM-CSF expression which further enhanced M1-like macrophages polarization...
  10. Mathur P, Medicherla K, Chaudhary S, Patel M, Bagali P, Suravajhala P. Whole exome sequencing reveals rare variants linked to congenital pouch colon. Sci Rep. 2018;8:6646 pubmed publisher
  11. Jiang M, Chu Z. Comparative analysis of plant MKK gene family reveals novel expansion mechanism of the members and sheds new light on functional conservation. BMC Genomics. 2018;19:407 pubmed publisher
    ..Moreover, we also identified MKK3 integrated NTF2 domain that might have gradually lost the cytoplasmic-nuclear trafficking activity, which suggests ..
  12. Lu W, Chua M, So S. Suppression of ATAD2 inhibits hepatocellular carcinoma progression through activation of p53- and p38-mediated apoptotic signaling. Oncotarget. 2015;6:41722-35 pubmed publisher
    ..In HCC cells, we demonstrated that ATAD2 directly interacted with MKK3/6, which prevented p38 activation and therefore inhibited p38-mediated apoptosis...
  13. Mao X, Zhang J, Liu W, Yan S, Liu Q, Fu H, et al. The MKKK62-MKK3-MAPK7/14 module negatively regulates seed dormancy in rice. Rice (N Y). 2019;12:2 pubmed publisher
    ..The MAPK cascade is involved in many signal transduction pathways. Recently, MKK3 has been reported to be involved in the regulation of seed dormancy, but its mechanism of action is unclear...
  14. Yoshida H, Jono H, Kai H, Li J. The tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7. J Biol Chem. 2005;280:41111-21 pubmed
    ..by TLR2 ligands including peptidoglycan (PGN), MALP-2, and Pam3CSK4 induces activation of IKKs-IkappaBalpha and MKK3/6-p38 pathways not only by TRAF6 but also by TRAF7, a recently identified TRAF family member...
  15. Chakrabarti S, Poidevin M, Lemaitre B. The Drosophila MAPK p38c regulates oxidative stress and lipid homeostasis in the intestine. PLoS Genet. 2014;10:e1004659 pubmed publisher
    ..Our genetic analysis shows that p38c functions in a pathway with Mekk1 and Mkk3 to induce the phosphorylation of Atf-2, a transcription factor that controls Duox expression...
  16. Wang W, Chen J, Liao R, Deng Q, Zhou J, Huang S, et al. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol. 2002;22:3389-403 pubmed
    ..Constitutive activation of p38 by active MKK3 or MKK6 induces senescence...
  17. Otto K, Acharya S, Robinson V. Stress-activated kinase pathway alteration is a frequent event in bladder cancer. Urol Oncol. 2012;30:415-20 pubmed publisher
    ..T24, UMUC-3, J82, 5637, 253J, and 253J-BV) were analyzed by immunoblotting for the JNK and p38 MAPKs, as well as MKK3, MKK4, MKK6, and MKK7. Quantitative real time PCR was utilized to determine mRNA expression levels of the MAP2Ks...
  18. Velagapudi R, Aderogba M, Olajide O. Tiliroside, a dietary glycosidic flavonoid, inhibits TRAF-6/NF-?B/p38-mediated neuroinflammation in activated BV2 microglia. Biochim Biophys Acta. 2014;1840:3311-9 pubmed publisher
    ..iNOS, COX-2, phospho-p65, phospho-I?B?, phospho-IKK?, phospho-p38, phospho-MK2, phosopho-MKK3/6 and TRAF-6 were determined by western blot analysis...
  19. Jang Y, Son H, Kim J, Jung C, Ahn J, Hur J, et al. Coffee consumption promotes skeletal muscle hypertrophy and myoblast differentiation. Food Funct. 2018;9:1102-1111 pubmed publisher
    ..Coffee activated the MKK3/6-p38 pathway and upregulated PGC-1?, which may play a role in promoting myogenic differentiation and myogenin ..
  20. Rampoldi L, Zimbello R, Bortoluzzi S, Tiso N, Valle G, Lanfranchi G, et al. Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5. Cytogenet Cell Genet. 1997;78:301-3 pubmed
    ..We report the chromosomal localization of the human MEK1, MEK3, MEK4 and MEKK5 genes, involved in the MAPK cascade...
  21. Zhang C, Li J, Aji T, Li L, Bi X, Yang N, et al. Identification of Functional MKK3/6 and MEK1/2 Homologs from Echinococcus granulosus and Investigation of Protoscolecidal Activity of Mitogen-Activated Protein Kinase Signaling Pathway Inhibitors In Vitro and In Vivo. Antimicrob Agents Chemother. 2019;63: pubmed publisher
    ..In this study, we identified two new members of mitogen-activated protein kinase (MAPK) cascades, MKK3/6 and MEK1/2 homologs (termed EgMKK1 and EgMKK2, respectively), from E...
  22. Ben Levy R, Hooper S, Wilson R, Paterson H, Marshall C. Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr Biol. 1998;8:1049-57 pubmed
    ..The p38 activators MKK3 and MKK6 were present in both the nucleus and the cytoplasm, consistent with a role in activating p38 in the ..
  23. Lachén Montes M, González Morales A, Iloro I, Elortza F, Ferrer I, Gveric D, et al. Unveiling the olfactory proteostatic disarrangement in Parkinson's disease by proteome-wide profiling. Neurobiol Aging. 2019;73:123-134 pubmed publisher
    ..In addition, network-driven proteomics revealed a modulation in ERK1/2, MKK3/6, and PDK1/PKC signaling axes...
  24. Yoon K, Cho J, Lee J, Kang Y, Chae J, Kim Y, et al. CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1. Proc Natl Acad Sci U S A. 2009;106:17389-94 pubmed publisher
    ..These observations thus suggest that CIB1 functions as a Ca(2+)-sensitive negative regulator of ASK1-mediated signaling events. ..
  25. Greenblatt M, Kim J, Oh H, Park K, Choo M, Sano Y, et al. p38α MAPK is required for tooth morphogenesis and enamel secretion. J Biol Chem. 2015;290:284-95 pubmed publisher
    ..Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects, implying that MKK6 functions as an upstream kinase of p38α in ectodermal ..
  26. Lee H. Mitogen-Activated Protein Kinase Kinase 3 Is Required for Regulation during Dark-Light Transition. Mol Cells. 2015;38:651-6 pubmed publisher
    ..In analyses of mitogen-activated protein kinase kinase (MAPKK, also called MKK) mutants, the mkk3 mutant has shown both a hypersensitive response in plant hormone gibberellin (GA) and a less sensitive response in ..
  27. Liu T, Warburton R, Hill N, Kayyali U. Anthrax lethal toxin-induced lung injury and treatment by activating MK2. J Appl Physiol (1985). 2015;119:412-9 pubmed publisher
    ..Recently, we showed that LeTx inactivation of p38 MAP kinase signaling via degradation of MKK3 in pulmonary vascular endothelial cells can be linked to compromise of the endothelial permeability barrier...
  28. Tanaka T, Iino M, Goto K. Sec6 enhances cell migration and suppresses apoptosis by elevating the phosphorylation of p38 MAPK, MK2, and HSP27. Cell Signal. 2018;49:1-16 pubmed publisher
    ..study, we observed that Sec6 increased the phosphorylation of p38 MAPK through the activation of MAPK kinase 3/6 (MKK3/6)...
  29. Zhou Q, Deng C, Li Z, Chen J, Yao K, Huang K, et al. Molecular characterization and integrative genomic analysis of a panel of newly established penile cancer cell lines. Cell Death Dis. 2018;9:684 pubmed publisher
  30. Tebaldi T, Zaccara S, Alessandrini F, Bisio A, Ciribilli Y, Inga A. Whole-genome cartography of p53 response elements ranked on transactivation potential. BMC Genomics. 2015;16:464 pubmed publisher
    ..Our approach is distinct from, and complementary to, existing methods designed to identify p53 response elements. p53retriever is available as an R package at: http://tomateba.github.io/p53retriever . ..
  31. Mo J, Jung J, Yoon J, Hong J, Kim M, Ann E, et al. DJ-1 modulates the p38 mitogen-activated protein kinase pathway through physical interaction with apoptosis signal-regulating kinase 1. J Cell Biochem. 2010;110:229-37 pubmed publisher
    ..and kinase studies have revealed that ASK1 is the direct target of DJ-1, whereas it has shown no effect on either MKK3 or p38. DJ-1 blocked both the homo-oligomerization of ASK1 and inhibited ASK1 activity...
  32. Yang P, Fu S, Cao Z, Liao H, Huo Z, Pan Y, et al. Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy. Toxicol Appl Pharmacol. 2015;288:269-79 pubmed publisher
    ..protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in ..
  33. Xu J, Tang S, Yin B, Sun J, Bao E. Co-enzyme Q10 upregulates Hsp70 and protects chicken primary myocardial cells under in vitro heat stress via PKC/MAPK. Mol Cell Biochem. 2018;449:195-206 pubmed publisher
    ..Co-enzyme Q10 upregulates the expression of p-MEK3/6 and p-MEK4, but not p-MEK7 during heat stress...
  34. Schonhoff C, Park S, Webster C, Anwer M. p38 MAPK ? and ? isoforms differentially regulate plasma membrane localization of MRP2. Am J Physiol Gastrointest Liver Physiol. 2016;310:G999-G1005 pubmed publisher
    ..could be mediated via different p38 MAPK isoforms (? and ?) that are activated differentially by upstream kinases (MKK3, MKK4, and MKK6)...
  35. Yao X, Wang Y, Zhang D. microRNA-21 Confers Neuroprotection Against Cerebral Ischemia-Reperfusion Injury and Alleviates Blood-Brain Barrier Disruption in Rats via the MAPK Signaling Pathway. J Mol Neurosci. 2018;65:43-53 pubmed publisher
  36. Danquah A, de Zélicourt A, Boudsocq M, Neubauer J, Frei dit Frey N, Leonhardt N, et al. Identification and characterization of an ABA-activated MAP kinase cascade in Arabidopsis thaliana. Plant J. 2015;82:232-44 pubmed publisher
    ..and reconstituted in vivo a complete ABA-activated MAPK cascade, composed of the MAP3Ks MAP3K17/18, the MAP2K MKK3 and the four C group MAPKs MPK1/2/7/14...
  37. Torada A, Koike M, Ogawa T, Takenouchi Y, Tadamura K, Wu J, et al. A Causal Gene for Seed Dormancy on Wheat Chromosome 4A Encodes a MAP Kinase Kinase. Curr Biol. 2016;26:782-7 pubmed publisher
    ..6 cM region [14]. Here, we identified a mitogen-activated protein kinase kinase 3 (MKK3) gene (designated TaMKK3-A) by a map-based approach as a candidate gene for the seed dormancy locus Phs1 ..
  38. 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
    ..experiments were used to examine the regulation by MEKK2 and MEKK3 of the dual specificity MAP kinase kinases, MKK3 and MKK4...
  39. Cederbaum A, Lu Y, Wang X, Wu D. Synergistic toxic interactions between CYP2E1, LPS/TNFα, and JNK/p38 MAP kinase and their implications in alcohol-induced liver injury. Adv Exp Med Biol. 2015;815:145-72 pubmed publisher
    ..This activation of ASK-1 is followed by activation of the mitogen-activated kinase kinases MKK3/MKK6 and MKK4/MMK7 and subsequently p38 and JNK MAP kinases...
  40. Srivastava A, McGinniss J, Wong Y, Shinn A, Lam T, Lee P, et al. MKK3 deletion improves mitochondrial quality. Free Radic Biol Med. 2015;87:373-84 pubmed publisher
    ..Mitochondria have been shown to influence the outcome of septic injury. We have previously shown that MAP kinase kinase 3 (MKK3)(-/-) mice are resistant to septic injury and MKK3(-/-) macrophages have improved mitochondrial ..
  41. 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
    ..Here, we show that p62 is phosphorylated via a cascade that includes MEK3/6 and p38δ and is driven by the PB1-containing kinase MEKK3...
  42. Wang Y, Cui R, Zhang X, Qiao Y, Liu X, Chang Y, et al. SIRT1 increases YAP- and MKK3-dependent p38 phosphorylation in mouse liver and human hepatocellular carcinoma. Oncotarget. 2016;7:11284-98 pubmed publisher
    ..SIRT1 increased phosphorylation and nuclear accumulation of p38, possibly by increasing MKK3 expression. SIRT1 also induced YAP expression, which in turn increased MKK3 transcription...
  43. Dong W, Embury C, Lu Y, Whitmire S, Dyavarshetty B, Gelbard H, et al. The mixed-lineage kinase 3 inhibitor URMC-099 facilitates microglial amyloid-β degradation. J Neuroinflammation. 2016;13:184 pubmed publisher
    ..murine microglia were investigated for phosphorylated mitogen-activated protein kinase kinase (MKK)3, MKK4 (p-MKK3, p-MKK4), p38 (p-p38), and JNK (p-JNK)...
  44. Li X, Shen J, Jiang Y, Shen T, You L, Sun X, et al. Anti-Inflammatory Effects of Chloranthalactone B in LPS-Stimulated RAW264.7 Cells. Int J Mol Sci. 2016;17: pubmed
    ..Furthermore, CTB suppressed the phosphorylation of MKK3/6 by targeting the binding sites via formation of hydrogen bonds...
  45. Niino T, Tago K, Yasuda D, Takahashi K, Mashino T, Tamura H, et al. A 5-hydroxyoxindole derivative attenuates LPS-induced inflammatory responses by activating the p38-Nrf2 signaling axis. Biochem Pharmacol. 2018;155:182-197 pubmed publisher
    ..Furthermore, 5-HI induced the activation of the MKK3/6-p38 pathway, which is required for the transcriptional activation of Nrf2...
  46. Pham H, Vincenti R, Slice L. COX-2 promoter activation by AT1R-Gq-PAK-p38beta signaling in intestinal epithelial cells. Biochim Biophys Acta. 2008;1779:408-13 pubmed publisher
    ..Expression of constitutively active MKK6 EE but not MKK3 EE induced the COX-2 and Gal4-CREB promoters via p38MAPK...
  47. Kukkonen S, Martinez Viedma M, Kim N, Manrique M, Aldovini A. HIV-1 Tat second exon limits the extent of Tat-mediated modulation of interferon-stimulated genes in antigen presenting cells. Retrovirology. 2014;11:30 pubmed publisher
  48. Yeung Y, Yin S, Lu B, Fan S, Yang R, Bai R, et al. Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization. EBioMedicine. 2018;28:51-61 pubmed publisher
    ..In our present study, we found that gefitinib could activate YAP-MKK3/6-p38 MAPK-STAT3 signaling and induce tetraploidization in gefitinib-resistance cells...
  49. 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...
  50. Huang Y, Huang Q, Su H, Mai X, Feng E, Cao Z, et al. TAR DNA-binding protein 43 inhibits inflammatory response and protects chondrocyte function by modulating RACK1 expression in osteoarthritis. Biomed Pharmacother. 2017;85:362-371 pubmed publisher
    ..Critical genes were highly expressed in P38 MAPK/MKK3 proliferative signaling, but not in P38 MAPK/JNK MAPK signaling...
  51. Li Y, Cai H, Liu P, Wang C, Gao H, Wu C, et al. Arabidopsis MAPKKK18 positively regulates drought stress resistance via downstream MAPKK3. Biochem Biophys Res Commun. 2017;484:292-297 pubmed publisher
    ..Furthermore, MAPKKK18 mainly exerted its regulatory roles via downstream MAPKK3. These findings uncovered important roles for MAPKKK18 in drought resistance and expanded our understanding of the ..
  52. Wang Y, Dai X, Liu Y, Li J, Liu Z, Yin P, et al. MTUS1 silencing promotes E-selectin production through p38 MAPK-dependent CREB ubiquitination in endothelial cells. J Mol Cell Cardiol. 2016;101:1-10 pubmed publisher
    ..chemotactic protein-1 in ECs, which is accompanied with increased phosphorylation of p38 MAPK (Thr180/Tyr182), MKK3/6 (Ser 189) and I?B? (Ser 32)...
  53. Yang L, Wang B, Zhou Q, Wang Y, Liu X, Liu Z, et al. MicroRNA-21 prevents excessive inflammation and cardiac dysfunction after myocardial infarction through targeting KBTBD7. Cell Death Dis. 2018;9:769 pubmed publisher
    ..Furthermore, KBTBD7 interacted with MKK3/6 and promoted their activation, which in turn enhanced the activation of downstream p38 and NF-?B signaling ..
  54. Jia R, Ma J, Meng W, Wang N. Dihydromyricetin inhibits caerulin-induced TRAF3-p38 signaling activation and acute pancreatitis response. Biochem Biophys Res Commun. 2018;503:1696-1702 pubmed publisher
    ..inhibited caerulin-induced TRAF3 protein stabilization, TRAF3-mitogen-activated protein kinase kinase 3 (MKK3) association and following MKK3-p38 activation in BMDMs...
  55. Gupta P, Das P, Ukil A. Antileishmanial effect of 18β-glycyrrhetinic acid is mediated by Toll-like receptor-dependent canonical and noncanonical p38 activation. Antimicrob Agents Chemother. 2015;59:2531-9 pubmed publisher
    ..as well as studies with dominant-negative (DN) constructs revealed mitogen-activated protein kinase kinase 3 (MKK3) and MKK6 as the immediate upstream regulators of p38...
  56. Li Y, Li Z, Zhang C, Li P, Wu Y, Wang C, et al. Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling. Circulation. 2017;135:2041-2057 pubmed publisher
    ..These results suggest that positive modulation of cardiac fibroblast ATF3 may represent a novel therapeutic approach against hypertensive cardiac remodeling. ..
  57. Casar B, Sanz Moreno V, Yazicioglu M, Rodriguez J, Berciano M, Lafarga M, et al. Mxi2 promotes stimulus-independent ERK nuclear translocation. EMBO J. 2007;26:635-46 pubmed
    ..These results point to Mxi2 as a key spatial regulator for ERK1/2 and disclose an unprecedented stimulus-independent mechanism for ERK nuclear import. ..
  58. Behren A, Mühlen S, Acuna Sanhueza G, Schwager C, Plinkert P, Huber P, et al. Phenotype-assisted transcriptome analysis identifies FOXM1 downstream from Ras-MKK3-p38 to regulate in vitro cellular invasion. Oncogene. 2010;29:1519-30 pubmed publisher
    ..pathways, ERK, JNK, p38 and exert distinct cellular phenotypes, that is, apoptosis and invasion through the Ras-MKK3-p38-signaling cascade...
  59. Thapa D, Nichols C, Bassi R, Martin E, Verma S, Conte M, et al. TAB1-Induced Autoactivation of p38α Mitogen-Activated Protein Kinase Is Crucially Dependent on Threonine 185. Mol Cell Biol. 2018;38: pubmed publisher
    ..The first relies on dedicated dual-specificity kinases such as mitogen-activated protein kinase kinase (MAP2K) 3 (MKK3) or 6 (MKK6), which activate p38α by phosphorylating Thr180 and Tyr182 within the activation segment...
  60. Warr N, Siggers P, Carré G, Wells S, Greenfield A. Genetic Analyses Reveal Functions for MAP2K3 and MAP2K6 in Mouse Testis Determination. Biol Reprod. 2016;94:103 pubmed publisher
    ..25 days postcoitum. Our data suggest that MAP2K6 functions in mouse testis determination, via positive effects on Sry, and also indicate a minor role for MAP2K3. ..
  61. Stramucci L, Pranteda A, Bossi G. Insights of Crosstalk between p53 Protein and the MKK3/MKK6/p38 MAPK Signaling Pathway in Cancer. Cancers (Basel). 2018;10: pubmed publisher
    ..Recently, the kinase MKK3 emerged as a potential therapeutic target in different types of solid tumor being linked to mutant p53 gain-of-..
  62. Huang C, You J, Wu M, Hsu K. Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. J Biol Chem. 2004;279:12286-92 pubmed
    ..DHPG) activates p38 MAPK through G protein betagamma-subunit, small GTPase Rap1, and MAPK kinase 3/6 (MKK3/6), thus resulting in mGluR5-dependent LTD...
  63. Xie X, Song J, Li G. MiR-21a-5p suppresses bisphenol A-induced pre-adipocyte differentiation by targeting map2k3 through MKK3/p38/MAPK. Biochem Biophys Res Commun. 2016;473:140-146 pubmed publisher
    ..MiR-21a-5p overexpression inhibited the protein level of MKK3, but not in the mRNA level. Luciferase activity assay showed that miR-21a-5p directly targeted map2k3 3'-UTR...
  64. Matsuoka D, Yasufuku T, Furuya T, Nanmori T. An abscisic acid inducible Arabidopsis MAPKKK, MAPKKK18 regulates leaf senescence via its kinase activity. Plant Mol Biol. 2015;87:565-75 pubmed publisher
    ..Yeast two-hybrid analysis revealed that MAPKKKK18 interacted with MKK3, which interacted with C-group MAPK, MPK1/2/7...
  65. Zhang B, Han H, Fu S, Yang P, Gu Z, Zhou Q, et al. Dehydroeffusol inhibits gastric cancer cell growth and tumorigenicity by selectively inducing tumor-suppressive endoplasmic reticulum stress and a moderate apoptosis. Biochem Pharmacol. 2016;104:8-18 pubmed publisher
    ..In addition, DHE markedly activated the stress response signaling pathway MEKK4-MKK3/6-p38-DDIT3, but significantly inhibited ERK signaling...
  66. Takahashi M, Gotoh Y, Isagawa T, Nishimura T, Goyama E, Kim H, et al. Regulation of a mitogen-activated protein kinase kinase kinase, MLTK by PKN. J Biochem. 2003;133:181-7 pubmed
    ..These results suggest that PKNalpha functions as not only an upstream activator of MLTKalpha but also a putative scaffold protein for the p38gamma MAPK signaling pathway. ..
  67. Lai R, Gu M, Jiang W, Lin W, Xu P, Liu Z, et al. Raf Kinase Inhibitor Protein Preferentially Promotes TLR3-Triggered Signaling and Inflammation. J Immunol. 2017;198:4086-4095 pubmed publisher
    ..Simultaneously, RKIP enhances the Poly(I:C)-induced interaction between TGF-?-activated kinase 1 and MAPK kinase 3 (MKK3), thus promoting MKK3/6 and p38 activation...
  68. Enders T, Frick E, Strader L. An Arabidopsis kinase cascade influences auxin-responsive cell expansion. Plant J. 2017;92:68-81 pubmed publisher
    ..Further, mutants defective in the upstream MAP kinase kinase MKK3 also display hypersensitivity in auxin-responsive cell expansion assays, suggesting that this MPK cascade affects ..
  69. Yan A, Chen Y, Chen S, Li S, Zhang Y, Jia J, et al. Leptin Stimulates Prolactin mRNA Expression in the Goldfish Pituitary through a Combination of the PI3K/Akt/mTOR, MKK3/6/p38MAPK and MEK1/2/ERK1/2 Signalling Pathways. Int J Mol Sci. 2017;18: pubmed publisher
    ..Moreover, the PI3K/Akt/mTOR, MKK3/6/p38MAPK, and MEK1/2/ERK1/2-but not JAK2/STAT 1, 3 and 5 cascades-were involved in leptin-induced PRL mRNA expression in the goldfish pituitary. ..
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    ..Using map-based cloning, we identified the causal gene for Qsd2-AK as Mitogen-activated Protein Kinase Kinase 3 (MKK3)...
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    ..In this study, we identified a novel MKK3/6 gene in the sea cucumber Apostichopus japonicus (designated as AjMKK3/6) by transcriptome database mining and ..
  72. Tomita K, Kabashima A, Freeman B, Bronk S, Hirsova P, Ibrahim S. Mixed Lineage Kinase 3 Mediates the Induction of CXCL10 by a STAT1-Dependent Mechanism During Hepatocyte Lipotoxicity. J Cell Biochem. 2017;118:3249-3259 pubmed publisher
    ..by a mitogen activated protein kinase (MAPK) signaling cascade consisting of a relay kinase module of MLK3, MKK3/6, and p38...
  73. Grimsey N, Aguilar B, Smith T, Le P, Soohoo A, Puthenveedu M, et al. Ubiquitin plays an atypical role in GPCR-induced p38 MAP kinase activation on endosomes. J Cell Biol. 2015;210:1117-31 pubmed publisher
    ..TAB2 associated with TAB1, which induced p38 activation independent of MKK3 and MKK6. The P2Y1 purinergic GPCR also stimulated p38 activation via NEDD4-2-mediated ubiquitination and TAB1-TAB2...
  74. Huang D, Li X, Sun L, Huang P, Ying H, Wang H, et al. Regulation of Hippo signalling by p38 signalling. J Mol Cell Biol. 2016;8:328-37 pubmed publisher
    ..Lastly, we show that p38 signalling regulates Hippo signalling in mammalian cell lines. The Lic homologue MKK3 promotes nuclear localization of YAP via the actin cytoskeleton...
  75. 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
    ..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-regulated ..
  76. Han S, Lim T, Kim J, Yang H, Oh D, Yoon Park J, et al. The Ginsenoside Derivative 20(S)-Protopanaxadiol Inhibits Solar Ultraviolet Light-Induced Matrix Metalloproteinase-1 Expression. J Cell Biochem. 2017;118:3756-3764 pubmed publisher
    ..Two upstream signaling pathways for AP-1, the MEK1/2-ERK1/2-p90RSK and MEK3/6-p38 pathways, were also suppressed...
  77. Hou L, Gu W, Zhu H, Yao W, Wang W, Meng Q. Spiroplasma eriocheiris induces mouse 3T6-Swiss albino cell apoptosis that associated with the infection mechanism. Mol Immunol. 2017;91:75-85 pubmed publisher
    ..of microarray, eight focal adhesion (?-Catenin, Parvin, Grb2 and ERK) and MAPK signaling pathway (FGFR, Grb2, ERK, MKK3, p38 and JNK) genes and the housekeeping gene GAPDH were assayed by qPCR and Western blot to confirm the results...
  78. Fan S, Meng Q, Laterra J, Rosen E. Role of Src signal transduction pathways in scatter factor-mediated cellular protection. J Biol Chem. 2009;284:7561-77 pubmed publisher
    ..to stimulate Akt and IkappaB kinase activity; and Src-mediated stimulation of NF-kappaB was due, in part, to a Rac1/MKK3/6/p38 pathway and was Akt-dependent. SF caused the activation of Src and the Rac1 effector Pak1...
  79. Ramgolam V, Degregorio S, Rao G, Collinge M, Subaran S, Markovic Plese S, et al. T cell LFA-1 engagement induces HuR-dependent cytokine mRNA stabilization through a Vav-1, Rac1/2, p38MAPK and MKK3 signaling cascade. PLoS ONE. 2010;5:e14450 pubmed publisher
    ..in mouse splenic T cells was dependent on the phosphorylation of the mitogen-activated protein kinase kinase, MKK3, and its target MAP kinase p38MAPK, and lost in T cells obtained from MKK3 gene-deleted mice...
  80. Molho Pessach V, Ramot Y, Mogilevsky M, Cohen Daniel L, Eisenstein E, Abu Libdeh A, et al. Generalized verrucosis and abnormal T cell activation due to homozygous TAOK2 mutation. J Dermatol Sci. 2017;87:123-129 pubmed publisher
    ..molecular interaction; however, no impairment was observed in TAOK2 kinase activity toward its downstream target, MEK3/6, in patient's fibroblasts...
  81. Canfrán Duque A, Rotllan N, Zhang X, Fernández Fuertes M, Ramírez Hidalgo C, Araldi E, et al. Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. EMBO Mol Med. 2017;9:1244-1262 pubmed publisher
    ..we discovered that the absence of miR-21 in macrophages increases the expression of the miR-21 target gene, MKK3, promoting the induction of p38-CHOP and JNK signaling...
  82. Joassard O, Bélanger G, Karmouch J, Lunde J, Shukla A, Chopard A, et al. HuR Mediates Changes in the Stability of AChR β-Subunit mRNAs after Skeletal Muscle Denervation. J Neurosci. 2015;35:10949-62 pubmed publisher
    ..Finally, p38 MAPK, a pathway known to activate HuR, was induced following denervation as a result of MKK3/6 activation and a decrease in MKP-1 expression, thereby leading to an increase in the stability of AChR β-..
  83. Feng H, Gerilechaogetu F, Golden H, Nizamutdinov D, Foster D, Glaser S, et al. p38α MAPK inhibits stretch-induced JNK activation in cardiac myocytes through MKP-1. Int J Cardiol. 2016;203:145-55 pubmed publisher
    ..Expression of constitutively-active MKK3 (MKK3CA), the upstream activator of p38, abolished JNK phosphorylation in both basal and stretched NRVM...
  84. Yoon J, Mo J, Kim M, Ann E, Ahn J, Jo E, et al. LRRK2 functions as a scaffolding kinase of ASK1-mediated neuronal cell death. Biochim Biophys Acta Mol Cell Res. 2017;1864:2356-2368 pubmed publisher
    ..and kinase assays showed that LRRK2 acted as a scaffolding protein by interacting with each components of the ASK1-MKK3/6-p38 MAPK pathway through its specific domains and increasing the proximity to downstream targets...
  85. Raingeaud J, Whitmarsh A, Barrett T, Derijard B, Davis R. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996;16:1247-55 pubmed
    ..To test this hypothesis, we constructed expression vectors for activated MKK3 and MKK6, two MAP kinase kinases that phosphorylate and activate p38 MAP kinase...
  86. Li L, Liu Q, Xiong X, Liu J, Lai X, Cheng C, et al. Neuroglobin promotes neurite outgrowth via differential binding to PTEN and Akt. Mol Neurobiol. 2014;49:149-62 pubmed publisher
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    ..In this context, we have studied the role played by Mitogen activated protein (MAP) kinase kinase 3 (MKK3), a dual-specificity protein kinase, in cigarette smoke induced-inflammation and mitochondrial dysfunction...
  88. Liu Z, Lv Y, Zhang Y, Liu F, Zhu L, Pan S, et al. Matrine-Type Alkaloids Inhibit Advanced Glycation End Products Induced Reactive Oxygen Species-Mediated Apoptosis of Aortic Endothelial Cells In Vivo and In Vitro by Targeting MKK3 and p38MAPK Signaling. J Am Heart Assoc. 2017;6: pubmed publisher
    ..production and inhibited endothelial cell apoptosis in vivo and in vitro by recovering phosphorylation of MKK3/6 and p38 MAPK, nuclear factor erythroid 2-related factor 2 nuclear translocation, and antioxidant response element ..
  89. Fleming Y, Armstrong C, Morrice N, Paterson A, Goedert M, Cohen P. Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. Biochem J. 2000;352 Pt 1:145-54 pubmed
    ..b>MKK3, MKK4 and MKK6 all show a strong preference for phosphorylation of the tyrosine residue of the Thr-Gly-Tyr motifs ..
  90. Shin I, Kim S, Song H, Kim H, Moon A. H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells. J Biol Chem. 2005;280:14675-83 pubmed
    ..Taken together, the present study elucidated the role of the Rac-MKK3/6-p38 pathway leading to H-Ras-specific induction of malignant progression in breast epithelial cells, providing ..
  91. Kim N, Kukkonen S, Gupta S, Aldovini A. Tat engagement of p38 MAP kinase and IRF7 pathways leads to activation of interferon-stimulated genes in antigen-presenting cells. Blood. 2013;121:4090-100 pubmed publisher
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    ..These genes and pathways might be potential targets for improving oxaliplatin treatment in colon cancer patients. ..