Available structures
PDBOrtholog search: PDBe RCSB
AliasesMAP3K3, MAPKKK3, MEKK3, mitogen-activated protein kinase kinase kinase 3
External IDsOMIM: 602539 MGI: 1346874 HomoloGene: 69110 GeneCards: MAP3K3
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 17: 63.62 – 63.7 MbChr 11: 105.98 – 106.05 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Mitogen-activated protein kinase kinase kinase 3 is an enzyme that in humans is encoded by the MAP3K3 gene,[5] which is located on the long arm of chromosome 17 (17q23.3).[6]


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.

MAP3Ks are involved in regulating cell fate in response to external stimuli.[7] MAP3K3 directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NF-κB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed.[8] MEKK3 regulates the p38, JNK and ERK1/2 pathways.[7]


MAP3K3 has been shown to interact with [SQSTM1/p62],:

MAP3K3 in cancer

Two SNPs in the MAP3K3 gene were found as candidates for association with colon and rectal cancers.[15]

MEKK3 is highly expressed in 4 ovarian cancer cell lines (OVCA429, Hey, DOV13, and SKOv3). This expression level is significantly higher in those cancer cells when compared to normal cells. MEKK3 expression levels are comparable to IKK kinase activities, which also relate to activation of NFκB. High expression of MEKK3 in most of these ovarian cancer cells supposedly activate IKK kinase activity, which lead to increased levels of active NFκB. Also, MEKK3 interacts with AKT to activate NFκB. Genes related to cell survival and anti-apoptosis have increased expression in most cancer cells with high levels of MEKK3. This is probably due to constitutive activation of NFκB, which will regulate those genes. In this sense, knockdown of MEKK3 caused ovarian cancer cells to be more sensitive to drugs.[10]

MEKK3 also interacts with BRCA1. Knocking down BRCA1 resulted in inhibited MEKK3 kinase activity. The drug paclitaxel induces MEKK3 activity and it requires functional BRCA1 to do it. It was observed that in a breast cancer cell line BRCA1-deficient (HCC1937), paclitaxel was unable to activate MEKK3. Paclitaxel may be inducing stress-response through the MEKK3/JNK/p38/MAPK pathway, but not in mutated BRCA1 cells.[9]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198909 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020700 - 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. ^ Ellinger-Ziegelbauer H, Brown K, Kelly K, Siebenlist U (Jan 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". The Journal of Biological Chemistry. 272 (5): 2668–74. doi:10.1074/jbc.272.5.2668. PMID 9006902.
  6. ^ MAP3K3 in GeneCards – The Human Gene Compendium.
  7. ^ a b Craig EA, Stevens MV, Vaillancourt RR, et al. (2008). "MAP3Ks as central regulators of cell fate during development". Developmental Dynamics. 237 (11): 3102–14. doi:10.1002/dvdy.21750. PMID 18855897. S2CID 876964.
  8. ^ "Entrez Gene: MAP3K3 mitogen-activated protein kinase kinase kinase 3".
  9. ^ a b Gilmore PM, McCabe N, Quinn JE, Kennedy RD, Gorski JJ, Andrews HN, McWilliams S, Carty M, Mullan PB, Duprex WP, Liu ET, Johnston PG, Harkin DP (Jun 2004). "BRCA1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3". Cancer Research. 64 (12): 4148–54. doi:10.1158/0008-5472.CAN-03-4080. PMID 15205325.
  10. ^ a b Samanta AK, Huang HJ, Le XF, Mao W, Lu KH, Bast RC, Liao WS (Sep 2009). "MEKK3 expression correlates with nuclear factor kappa B activity and with expression of antiapoptotic genes in serous ovarian carcinoma". Cancer. 115 (17): 3897–908. doi:10.1002/cncr.24445. PMC 3061353. PMID 19517469.
  11. ^ Che W, Lerner-Marmarosh N, Huang Q, Osawa M, Ohta S, Yoshizumi M, Glassman M, Lee JD, Yan C, Berk BC, Abe J (Jun 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". Circulation Research. 90 (11): 1222–30. doi:10.1161/01.RES.0000021127.83364.7D. PMID 12065326.
  12. ^ Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, Gelfand EW, Johnson GL (Feb 2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". The Journal of Biological Chemistry. 276 (7): 5093–100. doi:10.1074/jbc.M003719200. PMID 11073940.
  13. ^ Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G (Feb 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216. S2CID 11683986.
  14. ^ Fanger GR, Widmann C, Porter AC, Sather S, Johnson GL, Vaillancourt RR (Feb 1998). "14-3-3 proteins interact with specific MEK kinases". The Journal of Biological Chemistry. 273 (6): 3476–83. doi:10.1074/jbc.273.6.3476. PMID 9452471.
  15. ^ Slattery ML, Lundgreen A, Wolff RK (2012). "MAP kinase genes and colon and rectal cancer". Carcinogenesis. 33 (12): 2398–408. doi:10.1093/carcin/bgs305. PMC 3510742. PMID 23027623.

Further reading