MAP3K3

Mitogen-activated protein kinase kinase kinase 3

PDB rendering based on 2c60.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
2C60, 2JRH, 2O2V, 2PPH

Identifiers

Symbols

MAP3K3 ; MAPKKK3; MEKK3

External IDs

OMIM: 602539 MGI: 1346874 HomoloGene: 69110 IUPHAR: 2078 ChEMBL: 5970 GeneCards: MAP3K3 Gene

EC number

2.7.11.25

Gene ontology
Molecular function	• protein kinase activity • MAP kinase kinase kinase activity • protein binding • ATP binding • metal ion binding
Cellular component	• cytosol
Biological process	• MAPK cascade • activation of MAPKK activity • intracellular signal transduction • positive regulation of I-kappaB kinase/NF-kappaB signaling • protein autophosphorylation
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 17:
63.62 – 63.7 Mb

Chr 11:
106.08 – 106.16 Mb

PubMed search

Mitogen-activated protein kinase kinase kinase 3 is an enzyme that in humans is encoded by the MAP3K3 gene.^[1]

This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse Mekk3. Its catalytic domain is closely related to those of several other kinases, including mouse Mekk2, tobacco NPK, and yeast Ste11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed. This protein directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively; it does not regulate the p38 pathway. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NFKB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed.^[2]

Interactions

MAP3K3 has been shown to interact with [SQSTM1/p62], MAP2K5,^[3]^[4] YWHAE,^[5] GAB1^[6] and BRCA1.^[7]

References

↑ Ellinger-Ziegelbauer H, Brown K, Kelly K, Siebenlist U (March 1997). "Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative". J Biol Chem 272 (5): 2668–74. doi:10.1074/jbc.272.5.2668. PMID 9006902.
↑ "Entrez Gene: MAP3K3 mitogen-activated protein kinase kinase kinase 3".
↑ Sun, W; Kesavan K; Schaefer B C; Garrington T P; Ware M; Johnson N L; Gelfand E W; Johnson G L (February 2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". J. Biol. Chem. (United States) 276 (7): 5093–100. doi:10.1074/jbc.M003719200. ISSN 0021-9258. PMID 11073940.
↑ Bouwmeester, Tewis; Bauch Angela, Ruffner Heinz, Angrand Pierre-Olivier, Bergamini Giovanna, Croughton Karen, Cruciat Cristina, Eberhard Dirk, Gagneur Julien, Ghidelli Sonja, Hopf Carsten, Huhse Bettina, Mangano Raffaella, Michon Anne-Marie, Schirle Markus, Schlegl Judith, Schwab Markus, Stein Martin A, Bauer Andreas, Casari Georg, Drewes Gerard, Gavin Anne-Claude, Jackson David B, Joberty Gerard, Neubauer Gitte, Rick Jens, Kuster Bernhard, Superti-Furga Giulio (February 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nat. Cell Biol. (England) 6 (2): 97–105. doi:10.1038/ncb1086. ISSN 1465-7392. PMID 14743216.
↑ Fanger, G R; Widmann C; Porter A C; Sather S; Johnson G L; Vaillancourt R R (February 1998). "14-3-3 proteins interact with specific MEK kinases". J. Biol. Chem. (UNITED STATES) 273 (6): 3476–83. doi:10.1074/jbc.273.6.3476. ISSN 0021-9258. PMID 9452471.
↑ Che, Wenyi; Lerner-Marmarosh Nicole, Huang Qunhua, Osawa Masaki, Ohta Shinsuke, Yoshizumi Masanori, Glassman Michael, Lee Jiing-Dwan, Yan Chen, Berk Bradford C, Abe Jun-Ichi (June 2002). "Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression". Circ. Res. (United States) 90 (11): 1222–30. doi:10.1161/01.RES.0000021127.83364.7D. PMID 12065326.
↑ Gilmore, Paula M; McCabe Nuala, Quinn Jennifer E, Kennedy Richard D, Gorski Julia J, Andrews Heather N, McWilliams Stewart, Carty Michael, Mullan Paul B, Duprex W Paul, Liu Edison T, Johnston Patrick G, Harkin D Paul (June 2004). "BRCA1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3". Cancer Res. (United States) 64 (12): 4148–54. doi:10.1158/0008-5472.CAN-03-4080. ISSN 0008-5472. PMID 15205325.

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Fanger GR, Widmann C, Porter AC et al. (1998). "14-3-3 proteins interact with specific MEK kinases.". J. Biol. Chem. 273 (6): 3476–83. doi:10.1074/jbc.273.6.3476. PMID 9452471.
Chao TH, Hayashi M, Tapping RI et al. (2000). "MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway.". J. Biol. Chem. 274 (51): 36035–8. doi:10.1074/jbc.274.51.36035. PMID 10593883.
Yang J, Boerm M, McCarty M et al. (2000). "Mekk3 is essential for early embryonic cardiovascular development.". Nat. Genet. 24 (3): 309–13. doi:10.1038/73550. PMID 10700190.
Sun W, Kesavan K, Schaefer BC et al. (2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway.". J. Biol. Chem. 276 (7): 5093–100. doi:10.1074/jbc.M003719200. PMID 11073940.
Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination.". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
Wiemann S, Weil B, Wellenreuther R et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs.". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
Simpson JC, Wellenreuther R, Poustka A et al. (2001). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing.". EMBO Rep. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
Yang J, Lin Y, Guo Z et al. (2001). "The essential role of MEKK3 in TNF-induced NF-kappaB activation.". Nat. Immunol. 2 (7): 620–4. doi:10.1038/89769. PMID 11429546.
Che W, Lerner-Marmarosh N, Huang Q et al. (2002). "Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression.". Circ. Res. 90 (11): 1222–30. doi:10.1161/01.RES.0000021127.83364.7D. PMID 12065326.
Lee CM, Onésime D, Reddy CD et al. (2002). "JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors.". Proc. Natl. Acad. Sci. U.S.A. 99 (22): 14189–94. doi:10.1073/pnas.232310199. PMC 137859. PMID 12391307.
Adams DG, Sachs NA, Vaillancourt RR (2002). "Phosphorylation of the stress-activated protein kinase, MEKK3, at serine 166.". Arch. Biochem. Biophys. 407 (1): 103–16. doi:10.1016/S0003-9861(02)00464-2. PMID 12392720.
Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Matsuda A, Suzuki Y, Honda G et al. (2003). "Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways.". Oncogene 22 (21): 3307–18. doi:10.1038/sj.onc.1206406. PMID 12761501.
Nakamura K, Johnson GL (2003). "PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway.". J. Biol. Chem. 278 (39): 36989–92. doi:10.1074/jbc.C300313200. PMID 12912994.
Huang Q, Yang J, Lin Y et al. (2004). "Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3.". Nat. Immunol. 5 (1): 98–103. doi:10.1038/ni1014. PMID 14661019.
Samanta AK, Huang HJ, Bast RC, Liao WS (2004). "Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappaB.". J. Biol. Chem. 279 (9): 7576–83. doi:10.1074/jbc.M311659200. PMID 14662759.
Stevens MV, Broka DM, Parker P, Rogowitz E, Vaillancourt RR, Camenisch TD (2008). "MEKK3 initiates Transforming Growth Factor beta 2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis.". Circ. Res. 103 (12): 1430–1440. doi:10.1161/CIRCRESAHA.108.180752. PMC 2728220. PMID 19008476.

PDB gallery

2c60: CRYSTAL STRUCTURE OF HUMAN MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 3 ISOFORM 2 PHOX DOMAIN AT 1.25 A RESOLUTION

2o2v: Crystal Structure of the Complex of Human Mitogen Activated Protein Kinase Kinase 5 Phox Domain (MAP2K5-phox) with Human Mitogen Activated Protein Kinase Kinase Kinase 3 (MAP3K3B-phox)

2pph: solution structure of human MEKK3 PB1 domain

MAP3K3

Interactions

References

Further reading