Available structures
PDBOrtholog search: PDBe RCSB
AliasesMAP2K4, JNKK, JNKK1, MAPKK4, MEK4, MKK4, PRKMK4, SAPKK-1, SAPKK1, SEK1, SERK1, SKK1, mitogen-activated protein kinase kinase 4
External IDsOMIM: 601335 MGI: 1346869 HomoloGene: 48159 GeneCards: MAP2K4
RefSeq (mRNA)


RefSeq (protein)


Location (UCSC)Chr 17: 12.02 – 12.14 MbChr 11: 65.58 – 65.68 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Dual-specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the MAP2K4 gene.[5]

MAP2K4 encodes a dual-specificity kinase that belongs to the Ser/Thr protein kinase family. MAP2K4 phosphorylates MAP kinases in response to various environmental stresses or mitogenic stimuli. MAPK8/JNK1, MAPK9/JNK2, and MAPK14/p38 are substrates for MAP2K4, but MAPK1/ERK2 and MAPK3/ERK1 are not phosphorylated by MAP2K4. Structurally, MAP2K4 contains a kinase domain that is phosphorylated and activated by MAP3K1(aka MEKK1).[6] MAP2K4 contains multiple amino acid sites that are phosphorylated and ubiquitinated.[7] Genetic studies using Map2k4 knockout mice revealed embryonic lethality, impaired hepatogenesis and defective liver formation.[8][9] Analysis of chimeric mice identified a role for Map2k4 in T cell cytokine production and proliferation.[10] Map2k4-deficient chimeric mice frequently develop lymphadenopathy.[11] MAP2K4 is altered in 1.97% of all human cancers.[12]


MAP2K4 has been shown to interact with:


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000065559 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000033352 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C, Mercurio F, et al. (April 1995). "Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2". Science. 268 (5208): 286–90. Bibcode:1995Sci...268..286L. doi:10.1126/science.7716521. PMID 7716521.
  6. ^ "P45985 | SWISS-MODEL Repository".
  7. ^ "MKK4 (human)". Retrieved 2020-10-28.
  8. ^ Nishina H, Vaz C, Billia P, Nghiem M, Sasaki T, De la Pompa JL, et al. (February 1999). "Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4". Development. 126 (3): 505–16. doi:10.1242/dev.126.3.505. PMID 9876179.
  9. ^ Ganiatsas S, Kwee L, Fujiwara Y, Perkins A, Ikeda T, Labow MA, Zon LI (June 1998). "SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis". Proceedings of the National Academy of Sciences of the United States of America. 95 (12): 6881–6. Bibcode:1998PNAS...95.6881G. doi:10.1073/pnas.95.12.6881. PMC 22670. PMID 9618507.
  10. ^ Nishina H, Bachmann M, Oliveira-dos-Santos AJ, Kozieradzki I, Fischer KD, Odermatt B, et al. (September 1997). "Impaired CD28-mediated interleukin 2 production and proliferation in stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes". The Journal of Experimental Medicine. 186 (6): 941–53. doi:10.1084/jem.186.6.941. PMC 2199046. PMID 9294148.
  11. ^ Swat W, Fujikawa K, Ganiatsas S, Yang D, Xavier RJ, Harris NL, et al. (May 1998). "SEK1/MKK4 is required for maintenance of a normal peripheral lymphoid compartment but not for lymphocyte development". Immunity. 8 (5): 625–34. doi:10.1016/s1074-7613(00)80567-1. PMID 9620683.
  12. ^ "MAP2K4 - My Cancer Genome". Retrieved 2020-12-26.
  13. ^ Xia Y, Wu Z, Su B, Murray B, Karin M (November 1998). "JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension". Genes & Development. 12 (21): 3369–81. doi:10.1101/gad.12.21.3369. PMC 317229. PMID 9808624.
  14. ^ Marti A, Luo Z, Cunningham C, Ohta Y, Hartwig J, Stossel TP, et al. (January 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". The Journal of Biological Chemistry. 272 (5): 2620–8. doi:10.1074/jbc.272.5.2620. PMID 9006895.
  15. ^ Lee CM, Onésime D, Reddy CD, Dhanasekaran N, Reddy EP (October 2002). "JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors". Proceedings of the National Academy of Sciences of the United States of America. 99 (22): 14189–94. Bibcode:2002PNAS...9914189L. doi:10.1073/pnas.232310199. PMC 137859. PMID 12391307.
  16. ^ a b Park HS, Kim MS, Huh SH, Park J, Chung J, Kang SS, Choi EJ (January 2002). "Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation". The Journal of Biological Chemistry. 277 (4): 2573–8. doi:10.1074/jbc.M110299200. PMID 11707464.
  17. ^ Chen Z, Cobb MH (May 2001). "Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2". The Journal of Biological Chemistry. 276 (19): 16070–5. doi:10.1074/jbc.M100681200. PMID 11279118.
  18. ^ Tournier C, Whitmarsh AJ, Cavanagh J, Barrett T, Davis RJ (July 1997). "Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase". Proceedings of the National Academy of Sciences of the United States of America. 94 (14): 7337–42. Bibcode:1997PNAS...94.7337T. doi:10.1073/pnas.94.14.7337. PMC 23822. PMID 9207092.
  19. ^ Cheng J, Yang J, Xia Y, Karin M, Su B (April 2000). "Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation". Molecular and Cellular Biology. 20 (7): 2334–42. doi:10.1128/MCB.20.7.2334-2342.2000. PMC 85399. PMID 10713157.
  20. ^ Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, et al. (November 1999). "JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway". Molecular and Cellular Biology. 19 (11): 7539–48. doi:10.1128/mcb.19.11.7539. PMC 84763. PMID 10523642.
  21. ^ Matsuura H, Nishitoh H, Takeda K, Matsuzawa A, Amagasa T, Ito M, et al. (October 2002). "Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade". The Journal of Biological Chemistry. 277 (43): 40703–9. doi:10.1074/jbc.M202004200. PMID 12189133.
  22. ^ Ahn YH, Kurie JM (October 2009). "MKK4/SEK1 is negatively regulated through a feedback loop involving the E3 ubiquitin ligase itch". The Journal of Biological Chemistry. 284 (43): 29399–29404. doi:10.1074/jbc.M109.044958. PMC 2785572. PMID 19737936.

Further reading

  • Lin, A (2006). "The JNK Signaling Pathway (Molecular Biology Intelligence Unit)". Landes Bioscience. 1: 1–97. ISBN 978-1587061202.