MAP2K4

Mitogen-activated protein kinase kinase 4
Rendering based on PDB 3ALN​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 3ALN​, 3ALO​, 3VUT​
Identifiers
Symbols	MAP2K4 ; JNKK; JNKK1; MAPKK4; MEK4; MKK4; PRKMK4; SAPKK-1; SAPKK1; SEK1; SERK1; SKK1
External IDs	OMIM: 601335 MGI: 1346869 HomoloGene: 48159 ChEMBL: 2897 GeneCards: MAP2K4 Gene
EC number	2.7.12.2
Gene ontology Molecular function • protein kinase activity • protein serine/threonine kinase activity • protein tyrosine kinase activity • protein binding • ATP binding • JUN kinase kinase activity Cellular component • intracellular • nucleus • cytosol Biological process • toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • apoptotic process • signal transduction • JNK cascade • activation of JUN kinase activity • peptidyl-tyrosine phosphorylation • toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • toll-like receptor 5 signaling pathway • toll-like receptor 9 signaling pathway • toll-like receptor 10 signaling pathway • TRIF-dependent toll-like receptor signaling pathway • Fc-epsilon receptor signaling pathway • toll-like receptor TLR1:TLR2 signaling pathway • toll-like receptor TLR6:TLR2 signaling pathway • innate immune response • stress-activated MAPK cascade • cellular response to mechanical stimulus Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	6416	26398
Ensembl	ENSG00000065559	ENSMUSG00000033352
UniProt	P45985	P47809
RefSeq (mRNA)	NM_001281435	NM_009157
RefSeq (protein)	NP_001268364	NP_033183
Location (UCSC)	Chr 17: 12.02 – 12.14 Mb	Chr 11: 65.69 – 65.79 Mb
PubMed search

Dual specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the MAP2K4 gene.^[1]

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.^[2]

Interactions

MAP2K4 has been shown to interact with FLNC,^[3] MAPK8,^{[4][5][6][7][8]} MAPK8IP3^[9][10] and AKT1.^[5]

References

1. Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C, Mercurio F, Johnson GL, Karin M (May 1995). "Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2". Science 268 (5208): 286–90. doi:10.1126/science.7716521. PMID 7716521.
2. "Entrez Gene: MAP2K4 mitogen-activated protein kinase kinase 4".
3. Marti, A; Luo Z; Cunningham C; Ohta Y; Hartwig J; Stossel T P; Kyriakis J M; Avruch J (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". J. Biol. Chem. (UNITED STATES) 272 (5): 2620–8. doi:10.1074/jbc.272.5.2620. ISSN 0021-9258. PMID 9006895.
4. Lee, Clement M; Onésime Djamila; Reddy C Damodara; Dhanasekaran N; Reddy E Premkumar (October 2002). "JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors". Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (22): 14189–94. doi:10.1073/pnas.232310199. ISSN 0027-8424. PMC 137859. PMID 12391307.
5. Park, Hee-Sae; Kim Mi-Sung; Huh Sung-Ho; Park Jihyun; Chung Jongkyeong; Kang Sang Sun; Choi Eui-Ju (January 2002). "Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation". J. Biol. Chem. (United States) 277 (4): 2573–8. doi:10.1074/jbc.M110299200. ISSN 0021-9258. PMID 11707464.
6. Chen, Z; Cobb M H (May 2001). "Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2". J. Biol. Chem. (United States) 276 (19): 16070–5. doi:10.1074/jbc.M100681200. ISSN 0021-9258. PMID 11279118.
7. Tournier, C; Whitmarsh A J; Cavanagh J; Barrett T; Davis R J (July 1997). "Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 94 (14): 7337–42. doi:10.1073/pnas.94.14.7337. ISSN 0027-8424. PMC 23822. PMID 9207092.
8. 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". Mol. Cell. Biol. (UNITED STATES) 20 (7): 2334–42. doi:10.1128/MCB.20.7.2334-2342.2000. ISSN 0270-7306. PMC 85399. PMID 10713157.
9. Ito, M; Yoshioka K; Akechi M; Yamashita S; Takamatsu N; Sugiyama K; Hibi M; Nakabeppu Y; Shiba T; Yamamoto K I (November 1999). "JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway". Mol. Cell. Biol. (UNITED STATES) 19 (11): 7539–48. doi:10.1128/mcb.19.11.7539. ISSN 0270-7306. PMC 84763. PMID 10523642.
10. Matsuura, Hiroshi; Nishitoh Hideki; Takeda Kohsuke; Matsuzawa Atsushi; Amagasa Teruo; Ito Michihiko; Yoshioka Katsuji; Ichijo Hidenori (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". J. Biol. Chem. (United States) 277 (43): 40703–9. doi:10.1074/jbc.M202004200. ISSN 0021-9258. PMID 12189133.

Further reading

• 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. doi:10.1126/science.7839144. 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. doi:10.1038/372798a0. 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. PMC 450280. 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. doi:10.1016/S0896-6273(00)80276-7. 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. doi:10.1074/jbc.272.5.2620. 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. doi:10.1074/jbc.272.22.14489. 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. doi:10.1074/jbc.272.24.15167. 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. doi:10.1074/jbc.272.51.32056. 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. doi:10.1074/jbc.273.21.12901. 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. doi:10.1016/S0378-1119(98)00158-9. 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. doi:10.1101/gad.12.21.3369. PMC 317229. 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 (3): 599–609. doi:10.1042/bj3360599. PMC 1219910. 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. doi:10.1074/jbc.274.15.10195. 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. doi:10.1126/science.285.5435.1920. PMID 10489373.