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Mitogen-activated protein kinase kinase 4
External IDs OMIM: 601335 MGI1346869 Homologene48159
Human Mouse
Entrez 6416 26398
Ensembl ENSG00000065559 ENSMUSG00000033352
Uniprot P45985 Q543X6
Refseq NM_003010 (mRNA)
NP_003001 (protein)
NM_009157 (mRNA)
NP_033183 (protein)
Location Chr 17: 11.86 - 11.99 Mb Chr 11: 65.5 - 65.6 Mb
Pubmed search [1] [2]

Mitogen-activated protein kinase kinase 4, also known as MAP2K4, is a human gene.

This gene encodes a dual specificity protein kinase that belongs to the Ser/Thr protein kinase family. This kinase is a direct activator of MAP kinases in response to various environmental stresses or mitogenic stimuli. It has been shown to activate MAPK8/JNK1, MAPK9/JNK2, and MAPK14/p38, but not MAPK1/ERK2 or MAPK3/ERK1. This kinase is phosphorylated, and thus activated by MAP3K1/MEKK. The knockout studies in mice suggested the roles of this kinase in mediating survival signal in T cell development, as well as in the organogenesis of liver.[1]


Further reading

  • Lin A, Minden A, Martinetto H, et al. (1995). "Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2.". Science 268 (5208): 286-90. PMID 7716521.
  • Dérijard B, Raingeaud J, Barrett T, et al. (1995). "Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms.". Science 267 (5198): 682-5. PMID 7839144.
  • Yan M, Dai T, Deak JC, et al. (1995). "Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1.". Nature 372 (6508): 798-800. PMID 7997270.
  • Salmeron A, Ahmad TB, Carlile GW, et al. (1996). "Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase.". EMBO J. 15 (4): 817-26. PMID 8631303.
  • Gale NW, Holland SJ, Valenzuela DM, et al. (1996). "Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis.". Neuron 17 (1): 9-19. PMID 8755474.
  • White RA, Hughes RT, Adkison LR, et al. (1996). "The gene encoding protein kinase SEK1 maps to mouse chromosome 11 and human chromosome 17.". Genomics 34 (3): 430-2. doi:10.1006/geno.1996.0309. PMID 8786147.
  • Nishina H, Fischer KD, Radvanyi L, et al. (1997). "Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3.". Nature 385 (6614): 350-3. doi:10.1038/385350a0. PMID 9002521.
  • Marti A, Luo Z, Cunningham C, et al. (1997). "Actin-binding protein-280 binds the stress-activated protein kinase (SAPK) activator SEK-1 and is required for tumor necrosis factor-alpha activation of SAPK in melanoma cells.". J. Biol. Chem. 272 (5): 2620-8. PMID 9006895.
  • Deacon K, Blank JL (1997). "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. 272 (22): 14489-96. PMID 9162092.
  • Hirai S, Katoh M, Terada M, et al. (1997). "MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/stress-activated protein kinase.". J. Biol. Chem. 272 (24): 15167-73. PMID 9182538.
  • Teng DH, Perry WL, Hogan JK, et al. (1997). "Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor.". Cancer Res. 57 (19): 4177-82. PMID 9331070.
  • Xu S, Cobb MH (1998). "MEKK1 binds directly to the c-Jun N-terminal kinases/stress-activated protein kinases.". J. Biol. Chem. 272 (51): 32056-60. PMID 9405400.
  • Guan Z, Buckman SY, Pentland AP, et al. (1998). "Induction of cyclooxygenase-2 by the activated MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway.". J. Biol. Chem. 273 (21): 12901-8. PMID 9582321.
  • Su GH, Hilgers W, Shekher MC, et al. (1998). "Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene.". Cancer Res. 58 (11): 2339-42. PMID 9622070.
  • Yang J, New L, Jiang Y, et al. (1998). "Molecular cloning and characterization of a human protein kinase that specifically activates c-Jun N-terminal kinase.". Gene 212 (1): 95-102. PMID 9661668.
  • Widegren U, Jiang XJ, Krook A, et al. (1998). "Divergent effects of exercise on metabolic and mitogenic signaling pathways in human skeletal muscle.". FASEB J. 12 (13): 1379-89. PMID 9761781.
  • Xia Y, Wu Z, Su B, et al. (1998). "JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension.". Genes Dev. 12 (21): 3369-81. PMID 9808624.
  • Chan-Hui PY, Weaver R (1999). "Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades.". Biochem. J. 336 ( Pt 3): 599-609. PMID 9841871.
  • Merritt SE, Mata M, Nihalani D, et al. (1999). "The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate.". J. Biol. Chem. 274 (15): 10195-202. PMID 10187804.
  • Orth K, Palmer LE, Bao ZQ, et al. (1999). "Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector.". Science 285 (5435): 1920-3. PMID 10489373.