MAP2K4

Main article: Mitogen-activated protein kinase kinase

Mitogen-activated protein kinase kinase 4

Rendering based on PDB 3ALN.

Available structures
PDB	3ALN, 3ALO

Identifiers

Symbols

MAP2K4; JNKK; JNKK1; MAPKK4; MEK4; MKK4; PRKMK4; SEK1; SERK1

External IDs

OMIM: 601335 MGI: 1346869 HomoloGene: 48159 GeneCards: MAP2K4 Gene

EC number

2.7.12.2

Gene Ontology
Molecular function	• nucleotide binding • protein kinase activity • protein serine/threonine kinase activity • protein tyrosine kinase activity • protein binding • ATP binding • JUN kinase kinase activity
Cellular component	• cytosol
Biological process	• toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • protein phosphorylation • signal transduction • JNK cascade • Toll signaling pathway • toll-like receptor 1 signaling pathway • toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • innate immune response • stress-activated MAPK cascade • cellular response to mechanical stimulus
Sources: Amigo / QuickGO

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 17:
11.92 – 12.05 Mb

Chr 11:
65.5 – 65.6 Mb

PubMed search

[1]

[2]

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

^ 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.
^ "Entrez Gene: MAP2K4 mitogen-activated protein kinase kinase 4". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6416.
^ Marti, A; Luo Z, Cunningham C, Ohta Y, Hartwig J, Stossel T P, Kyriakis J M, Avruch J (Jan. 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.
^ Lee, Clement M; Onésime Djamila, Reddy C Damodara, Dhanasekaran N, Reddy E Premkumar (Oct. 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=137859.
^ ^a ^b Park, Hee-Sae; Kim Mi-Sung, Huh Sung-Ho, Park Jihyun, Chung Jongkyeong, Kang Sang Sun, Choi Eui-Ju (Jan. 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.
^ 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.
^ Tournier, C; Whitmarsh A J, Cavanagh J, Barrett T, Davis R J (Jul. 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=23822.
^ Cheng, J; Yang J, Xia Y, Karin M, Su B (Apr. 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=85399.
^ Ito, M; Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, Hibi M, Nakabeppu Y, Shiba T, Yamamoto K I (Nov. 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. ISSN 0270-7306. PMC 84763. PMID 10523642. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=84763.
^ Matsuura, Hiroshi; Nishitoh Hideki, Takeda Kohsuke, Matsuzawa Atsushi, Amagasa Teruo, Ito Michihiko, Yoshioka Katsuji, Ichijo Hidenori (Oct. 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.

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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=450280.
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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=317229.
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. PMC 1219910. PMID 9841871. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1219910.
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.

Kinases: Serine/threonine-specific protein kinases (EC 2.7.11-12)

Serine/threonine-specific protein kinases (EC 2.7.11.1-EC 2.7.11.20)

Non-specific serine/threonine protein kinases (EC 2.7.11.1)	LATS1, LATS2, MAST1, MAST2, STK38, STK38L, CIT, ROCK1, SGK, SGK2, SGK3, Protein kinase B (AKT1, AKT2, AKT3), Ataxia telangiectasia mutated, Mammalian target of rapamycin, EIF-2 kinases (PKR, HRI, EIF2AK3, EIF2AK4), Wee1 (WEE1)

Pyruvate dehydrogenase kinase (EC 2.7.11.2)	PDK1, PDK2, PDK3

Dephospho-(reductase kinase) kinase (EC 2.7.11.3)	AMP-activated protein kinase α (PRKAA1, PRKAA2) · β (PRKAB1, PRKAB2) · γ (PRKAG1, PRKAG2, PRKAG3)

(3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring)) (EC 2.7.11.4)	BCKDK, BCKDHA, BCKDHB

(isocitrate dehydrogenase (NADP+)) kinase (EC 2.7.11.5)	IDH2, IDH3A, IDH3B, IDH3G

(tyrosine 3-monooxygenase) kinase (EC 2.7.11.6)	STK4

Myosin-heavy-chain kinase (EC 2.7.11.7)	Aurora kinase (Aurora A kinase, Aurora B kinase)

Fas-activated serine/threonine kinase (EC 2.7.11.8)	FASTK, STK10

Goodpasture-antigen-binding protein kinase (EC 2.7.11.9)	-

IκB kinase (EC 2.7.11.10)	CHUK, IKK2, TBK1, IKBKE, IKBKG, IKBKAP

cAMP-dependent protein kinase (EC 2.7.11.11)	Protein kinase A, PRKACG, PRKACB, PRKACA, PRKY

cGMP-dependent protein kinase (EC 2.7.11.12)	Protein kinase G, PRKG1

Protein kinase C (EC 2.7.11.13)	Protein kinase C, Protein kinase Cζ, PKC alpha, PRKCB1, PRKCD, PRKCE, PRKCH, PRKCG, PRKCI, PRKCQ, Protein kinase N1, PKN2, PKN3,

Rhodopsin kinase (EC 2.7.11.14)	Rhodopsin kinase

Beta adrenergic receptor kinase (EC 2.7.11.15)	Beta adrenergic receptor kinase, Beta adrenergic receptor kinase-2

G-protein coupled receptor kinases (EC 2.7.11.16)	GRK4, GRK5, GRK6

Ca2+/calmodulin-dependent (EC 2.7.11.17)	BRSK2, CAMK1, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CAMK4, MLCK, CASK, CHEK1, CHEK2, DAPK1, DAPK2, DAPK3, STK11, MAPKAPK2, MAPKAPK3, MAPKAPK5, MARK1, MARK2, MARK3, MARK4, MELK, MKNK1, MKNK2, NUAK1, NUAK2, OBSCN, PASK, PHKG1, PHKG2, PIM1, PIM2, PKD1, PRKD2, PRKD3, PSKH1, SNF1LK2, KIAA0999, STK40, SNF1LK, SNRK, SPEG, TSSK2, Kalirin, TRIB1, TRIB2, TRIB3, TRIO, Titin, DCLK1

Myosin light-chain kinase (EC 2.7.11.18)	MYLK, MYLK2, MYLK3, MYLK4

Phosphorylase kinase (EC 2.7.11.19)	PHKA1, PHKA2, PHKB, PHKG1, PHKG2

Elongation factor 2 kinase (EC 2.7.11.20)	EEF2K, STK19

Serine/threonine-specific protein kinases (EC 2.7.11.21-EC 2.7.11.30)

Polo kinase (EC 2.7.11.21)	PLK1, PLK2, PLK3, PLK4

Cyclin-dependent kinase (EC 2.7.11.22)	CDK1, CDK2, CDKL2, CDK3, CDK4, CDK5, CDKL5, CDK6, CDK7, CDK8, CDK9, CDK10, CDC2L5, CRKRS, PCTK1, PCTK2, PCTK3, PFTK1, CDC2L1

(RNA-polymerase)-subunit kinase (EC 2.7.11.23)	RPS6KA5, RPS6KA4, P70S6 kinase, P70-S6 Kinase 1, RPS6KB2, RPS6KA2, RPS6KA3, RPS6KA1, RPS6KC1

Mitogen-activated protein kinase (EC 2.7.11.24)	Extracellular signal-regulated (MAPK1, MAPK3, MAPK4, MAPK6, MAPK7, MAPK12, MAPK15), C-Jun N-terminal (MAPK8, MAPK9, MAPK10), P38 mitogen-activated protein (MAPK11, MAPK13, MAPK14)

MAP3K (EC 2.7.11.25)	MAP kinase kinase kinases (MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8) RAFs (ARAF, BRAF, KSR1, KSR2), MLKs (MAP3K12, MAP3K13, MAP3K9, MAP3K10, MAP3K11, MAP3K7, ZAK), CDC7, MAP3K14

Tau-protein kinase (EC 2.7.11.26)	TPK1, TTK, GSK-3

(acetyl-CoA carboxylase) kinase (EC 2.7.11.27)	-

Tropomyosin kinase (EC 2.7.11.28)	-

Low-density-lipoprotein receptor kinase (EC 2.7.11.29)	-

Receptor protein serine/threonine kinase (EC 2.7.11.30)	Bone morphogenetic protein receptors (BMPR1, BMPR1A, BMPR1B, BMPR2), ACVR1, ACVR1B, ACVR1C, ACVR2A, ACVR2B, ACVRL1, Anti-Müllerian hormone receptor

Dual-specificity kinases (EC 2.7.12)

MAP2K	MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7

B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6

MAP2K4

Interactions

References

Further reading