Gene Symbol: Map3k11
Description: mitogen-activated protein kinase kinase kinase 11
Alias: Mlk-3, Mlk3, RHOE, mitogen-activated protein kinase kinase kinase 11, mixed lineage kinase 3
Species: rat
Products:     Map3k11

Top Publications

  1. Miao B, Yin X, Pei D, Zhang Q, Zhang G. Neuroprotective effects of preconditioning ischemia on ischemic brain injury through down-regulating activation of JNK1/2 via N-methyl-D-aspartate receptor-mediated Akt1 activation. J Biol Chem. 2005;280:21693-9 pubmed
    ..In our present results, ischemic preconditioning could not only inhibit activations of mixed lineage kinase 3, JNK1/2, and c-Jun but also enhanced activation of Akt1...
  2. Leung I, Lassam N. Dimerization via tandem leucine zippers is essential for the activation of the mitogen-activated protein kinase kinase kinase, MLK-3. J Biol Chem. 1998;273:32408-15 pubmed
    ..Taken together, these findings indicate that dimerization plays a pivotal role in MLK-3 activation. ..
  3. Xu Z, Maroney A, Dobrzanski P, Kukekov N, Greene L. The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis. Mol Cell Biol. 2001;21:4713-24 pubmed
    ..We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and ..
  4. Mota M, Reeder M, Chernoff J, Bazenet C. Evidence for a role of mixed lineage kinases in neuronal apoptosis. J Neurosci. 2001;21:4949-57 pubmed
    ..The mixed lineage kinase 3 (MLK3) belongs to a family of mitogen-activated protein (MAP) kinase kinase kinases...
  5. Zhu Q, Xu Y, Du C, Hou X. SUMOylation of the kainate receptor subunit GluK2 contributes to the activation of the MLK3-JNK3 pathway following kainate stimulation. FEBS Lett. 2012;586:1259-64 pubmed publisher
    ..Over-expression of wild-type GluK2, but not SUMOylation-deficient mutant, significantly increased the activity of MLK3 and JNK3 after kainate stimulation...
  6. Chadee D, Kyriakis J. MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. Nat Cell Biol. 2004;6:770-6 pubmed
    ..Mixed lineage kinase-3 (MLK3) is a MAP3K that was thought to be a cytokine-activated, and comparatively selective, regulator of the JNK group of ..
  7. Kim K, Kim B, Xu Z, Kim S. Mixed lineage kinase 3 (MLK3)-activated p38 MAP kinase mediates transforming growth factor-beta-induced apoptosis in hepatoma cells. J Biol Chem. 2004;279:29478-84 pubmed
    ..We show here that the members of the mixed lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper-bearing kinase (DLK)) are expressed in FaO rat hepatoma cells and are likely to act ..
  8. Ganguly A, Oo T, Rzhetskaya M, Pratt R, Yarygina O, Momoi T, et al. CEP11004, a novel inhibitor of the mixed lineage kinases, suppresses apoptotic death in dopamine neurons of the substantia nigra induced by 6-hydroxydopamine. J Neurochem. 2004;88:469-80 pubmed
    ..We conclude that c-jun phosphorylation is a general feature of apoptosis in living dopamine neurons and that the mixed lineage kinases play a functional role as up-stream mediators of cell death in these neurons. ..
  9. Zhong J, Kyriakis J. Dissection of a signaling pathway by which pathogen-associated molecular patterns recruit the JNK and p38 MAPKs and trigger cytokine release. J Biol Chem. 2007;282:24246-54 pubmed
    ..Our results define a signaling pathway whereby PAMPs can trigger MAPK activation and gene expression. ..

More Information


  1. Gallo K, Mark M, Scadden D, Wang Z, Gu Q, Godowski P. Identification and characterization of SPRK, a novel src-homology 3 domain-containing proline-rich kinase with serine/threonine kinase activity. J Biol Chem. 1994;269:15092-100 pubmed
  2. Mishra R, Barthwal M, Sondarva G, Rana B, Wong L, Chatterjee M, et al. Glycogen synthase kinase-3beta induces neuronal cell death via direct phosphorylation of mixed lineage kinase 3. J Biol Chem. 2007;282:30393-405 pubmed
    b>Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase member that activates the c-Jun N-terminal kinase (JNK) pathway. Aberrant activation of MLK3 has been implicated in neurodegenerative diseases...
  3. Cuadrado A, Nebreda A. Mechanisms and functions of p38 MAPK signalling. Biochem J. 2010;429:403-17 pubmed publisher
    ..Finally, we discuss how genetic mouse models are facilitating the identification of physiological functions for p38 MAPKs, which may impinge on their eventual use as therapeutic targets. ..
  4. Zhang Q, Tian H, Fu X, Zhang G. Delayed activation and regulation of MKK7 in hippocampal CA1 region following global cerebral ischemia in rats. Life Sci. 2003;74:37-45 pubmed
    ..Consistent with the active phase, the interaction of MLK3, ASK1 and phospho-JNK with MKK7 was increased compared with sham control, as shown by coimmunoprecipitation ..
  5. Pei D, Guan Q, Sun Y, Zhang Q, Xu T, Zhang G. N-Acetylcysteine inhibit the translocation of mixed lineage kinase-3 from cytosol to plasma membrane during transient brain ischemia in rat hippocampus. Neurosci Lett. 2005;391:38-42 pubmed
    Mixed lineage kinase-3 (MLK3) is a recently described member of the MLK subfamily of Ser/Thr protein kinases that interacts with mitogen-activated protein kinase (MAPK) pathways...
  6. Zhao J, Pei D, Zhang Q, Zhang G. Down-regulation Cdc42 attenuates neuronal apoptosis through inhibiting MLK3/JNK3 cascade during ischemic reperfusion in rat hippocampus. Cell Signal. 2007;19:831-43 pubmed
    ..Here we reported that ischemia/reperfusion significantly elevated Cdc42 activity, enhanced assembly of the Cdc42-MLK3 complex and activation of JNK pathway...
  7. Sato Kunisada R, Yoshida N, Nakamura S, Uchiyama H, Matsumoto H. Enhanced Expression of miR-199b-5p Promotes Proliferation of Pancreatic ?-Cells by Down-Regulation of MLK3. Microrna. 2016;5:57-65 pubmed
    ..Target genes of miR-199b-5p were investigated and Mixed lineage kinase-3 (MLK3) was identified as one of the candidates since its expression was down-regulated through an interaction with miR-..
  8. Wang R, Zhang Q, Han D, Xu J, Lu Q, Zhang G. Inhibition of MLK3-MKK4/7-JNK1/2 pathway by Akt1 in exogenous estrogen-induced neuroprotection against transient global cerebral ischemia by a non-genomic mechanism in male rats. J Neurochem. 2006;99:1543-54 pubmed
    ..with beta-estradiol 3-benzoate (E2) enhanced Akt1 activation and reduced the activation of mixed-lineage kinase 3 (MLK3), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase 1/2 (JNK1/2) in the hippocampal ..
  9. Wang Q, Yin X, Liu Y, Zhang G. K252a suppresses neuronal cells apoptosis through inhibiting the translocation of Bax to mitochondria induced by the MLK3/JNK signaling after transient global brain ischemia in rat hippocampal CA1 subregion. J Recept Signal Transduct Res. 2011;31:307-13 pubmed publisher
    ..These findings imply that K252a induced neuroprotection against ischemia/reperfusion in rat hippocampal CA1 subregion via inhibiting the mitochondrial apoptosis pathway induced by JNK activation. ..
  10. Pan J, Zhang Q, Zhang G. The neuroprotective effects of K252a through inhibiting MLK3/MKK7/JNK3 signaling pathway on ischemic brain injury in rat hippocampal CA1 region. Neuroscience. 2005;131:147-59 pubmed
    ..These results indicated that cerebral ischemia induced the continuous activation of MLK3/MKK7/JNK3 cascade, which all had two active waves only in the CA1 region...
  11. Swenson K, Winkler K, Means A. A new identity for MLK3 as an NIMA-related, cell cycle-regulated kinase that is localized near centrosomes and influences microtubule organization. Mol Biol Cell. 2003;14:156-72 pubmed
    ..approach to search for proteins with homology to the noncatalytic region of NIMA and identified mixed lineage kinase 3 (MLK3)...
  12. Teramoto H, Coso O, Miyata H, Igishi T, Miki T, Gutkind J. Signaling from the small GTP-binding proteins Rac1 and Cdc42 to the c-Jun N-terminal kinase/stress-activated protein kinase pathway. A role for mixed lineage kinase 3/protein-tyrosine kinase 1, a novel member of the mixed lineage kinase family. J Biol Chem. 1996;271:27225-8 pubmed
    ..of homology to that in Pak1 that is involved in binding to Rac1 and Cdc42 led to the identification of mixed lineage kinase 3 (MLK3), also known as protein-tyrosine kinase 1, as a potential candidate for this function...
  13. Zhang Q, Pei D, Guan Q, Sun Y, Liu X, Zhang G. Crosstalk between PSD-95 and JIP1-mediated signaling modules: the mechanism of MLK3 activation in cerebral ischemia. Biochemistry. 2007;46:4006-16 pubmed
    Our previous study indicates that global ischemia facilitates the assembly of the GluR6.PSD-95.MLK3 signaling module, which in turn activated MLK3, leading to exacerbated ischemic neuron death...
  14. Zhang Q, Wang R, Han D, Dong Y, Brann D. Role of Rac1 GTPase in JNK signaling and delayed neuronal cell death following global cerebral ischemia. Brain Res. 2009;1265:138-47 pubmed publisher
    ..Rac1 has been shown to interact with POSH (plenty of SH3s), a scaffold protein that binds to and regulates MLK3 and JNK activation...
  15. Yu C, Li C, Pei D, Zong Y, Shi Q, Wen X, et al. Neuroprotection against transient focal cerebral ischemia and oxygen-glucose deprivation by interference with GluR6-PSD95 protein interaction. Neurochem Res. 2009;34:2008-21 pubmed publisher
    ..ischemic brain insult on rat middle cerebral artery occlusion (MACo) model enhances the assembly of the GluR6-PSD95-MLK3 module and facilitates the phosphorylation of JNK...
  16. Johnson G, Nakamura K. The c-jun kinase/stress-activated pathway: regulation, function and role in human disease. Biochim Biophys Acta. 2007;1773:1341-8 pubmed
    ..In this review, we present our current understanding of JNK regulation and their involvement in homeostasis and dysregulation in human disease. ..
  17. Han D, Zhang Q, Yong Liu -, Li C, Zong Y, Yu C, et al. Co-activation of GABA receptors inhibits the JNK3 apoptotic pathway via the disassembly of the GluR6-PSD95-MLK3 signaling module in cerebral ischemic-reperfusion. FEBS Lett. 2008;582:1298-306 pubmed publisher
    ..The agonists inhibited the increased assembly of the GluR6-PSD-95-MLK3 module induced by cerebral ischemia and the activation of the MLK3-MKK4/7-JNK3 cascade...
  18. Sproul A, Xu Z, Wilhelm M, Gire S, Greene L. Cbl negatively regulates JNK activation and cell death. Cell Res. 2009;19:950-61 pubmed publisher
    ..Apoptotic stimuli lead to loss of Cbl protein/activity, thereby removing a critical brake on JNK activation and on cell death. ..
  19. Hu S, Ye J, Zong Y, Sun C, Liu D, Wu Y, et al. S-nitrosylation of mixed lineage kinase 3 contributes to its activation after cerebral ischemia. J Biol Chem. 2012;287:2364-77 pubmed publisher
    Previous studies in our laboratory have shown that mixed lineage kinase 3 (MLK3) can be activated following global ischemia...
  20. Leung I, Lassam N. The kinase activation loop is the key to mixed lineage kinase-3 activation via both autophosphorylation and hematopoietic progenitor kinase 1 phosphorylation. J Biol Chem. 2001;276:1961-7 pubmed
    ..Interestingly, HPK1 also phosphorylated MLK-3 activation loop in vitro, and Ser281 was found to be the major phosphorylation site, indicating that HPK1 also activates MLK-3 via phosphorylation of the kinase activation loop. ..