MAP2K4

Main article: Mitogen-activated protein kinase kinase

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

MAP2K4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3ALN, 3ALO, 3VUT
Identifiers
Aliases	MAP2K4, JNKK, JNKK1, MAPKK4, MEK4, MKK4, PRKMK4, SAPKK-1, SAPKK1, SEK1, SERK1, SKK1, mitogen-activated protein kinase kinase 4
External IDs	OMIM: 601335; MGI: 1346869; HomoloGene: 48159; GeneCards: MAP2K4; OMA:MAP2K4 - orthologs
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17p12 Start 12,020,829 bp[1] End 12,143,830 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11 B3|11 40.53 cM Start 65,579,069 bp[2] End 65,679,123 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in lateral nuclear group of thalamus Brodmann area 46 postcentral gyrus orbitofrontal cortex Pars compacta middle temporal gyrus superior frontal gyrus prefrontal cortex Achilles tendon Brodmann area 23 Top expressed in dentate gyrus of hippocampal formation granule cell genital tubercle facial motor nucleus superior frontal gyrus primary visual cortex anterior horn of spinal cord secondary oocyte dorsomedial hypothalamic nucleus granulocyte paraventricular nucleus of hypothalamus More reference expression data BioGPS n/a
Gene ontology Molecular function transferase activity protein kinase activity nucleotide binding kinase activity protein binding protein tyrosine kinase activity ATP binding MAP kinase kinase activity JUN kinase kinase activity protein serine/threonine kinase activity mitogen-activated protein kinase kinase kinase binding Cellular component cytoplasm nucleus dendrite cytoplasm cytosol perikaryon axon Biological process phosphorylation MAPK cascade protein phosphorylation cellular response to mechanical stimulus response to wounding peptidyl-tyrosine phosphorylation signal transduction negative regulation of motor neuron apoptotic process apoptotic process cell growth involved in cardiac muscle cell development cellular response to sorbitol positive regulation of smooth muscle cell apoptotic process JNK cascade positive regulation of protein phosphorylation positive regulation of neuron apoptotic process positive regulation of DNA replication positive regulation of apoptotic process positive regulation of nitric-oxide synthase biosynthetic process regulation of mitotic cell cycle stress-activated protein kinase signaling cascade activation of protein kinase activity regulation of apoptotic process Fc-epsilon receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6416 26398 Ensembl ENSG00000065559 ENSMUSG00000033352 UniProt P45985 P47809 RefSeq (mRNA) NM_001281435 NM_003010 NM_009157 NM_001316367 NM_001316368 NM_001316369 NM_001362739 NM_001362740 RefSeq (protein) NP_001268364 NP_003001 NP_001303296 NP_001303297 NP_001303298 NP_033183 NP_001349668 NP_001349669 Location (UCSC) Chr 17: 12.02 – 12.14 Mb Chr 11: 65.58 – 65.68 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

Interactions

MAP2K4 has been shown to interact with:

• MAP3K1,^[13]
• FLNC,^[14]
• MAPK8,^{[15][16][17][18][19]}
• MAPK8IP3^[20][21] and
• AKT1.^[16]
• ITCH.^[22]

References

1. GRCh38: Ensembl release 89: ENSG00000065559 – Ensembl, May 2017
2. 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)". www.phosphosite.org. 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". www.mycancergenome.org. 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. 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. hdl:2297/2692. 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.