MAP3K3
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]
Function
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]
Interactions
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]
References
- GRCh38: Ensembl release 89: ENSG00000198909 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000020700 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 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.
- MAP3K3 in GeneCards – The Human Gene Compendium. https://www.genecards.org/cgi-bin/carddisp.pl?gene=MAP3K3
- 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.
- "Entrez Gene: MAP3K3 mitogen-activated protein kinase kinase kinase 3".
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- 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.
- Chao TH, Hayashi M, Tapping RI, Kato Y, Lee JD (Dec 1999). "MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway". The Journal of Biological Chemistry. 274 (51): 36035–8. doi:10.1074/jbc.274.51.36035. PMID 10593883.
- Yang J, Boerm M, McCarty M, Bucana C, Fidler IJ, Zhuang Y, Su B (Mar 2000). "Mekk3 is essential for early embryonic cardiovascular development". Nature Genetics. 24 (3): 309–13. doi:10.1038/73550. PMID 10700190. S2CID 23203939.
- 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.
- Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A (Mar 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
- Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (Sep 2000). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
- Yang J, Lin Y, Guo Z, Cheng J, Huang J, Deng L, Liao W, Chen Z, Liu Z, Su B (Jul 2001). "The essential role of MEKK3 in TNF-induced NF-kappaB activation". Nature Immunology. 2 (7): 620–4. doi:10.1038/89769. PMID 11429546. S2CID 22382563.
- 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.
- Lee CM, Onésime D, Reddy CD, Dhanasekaran N, Reddy EP (Oct 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.
- Adams DG, Sachs NA, Vaillancourt RR (Nov 2002). "Phosphorylation of the stress-activated protein kinase, MEKK3, at serine 166". Archives of Biochemistry and Biophysics. 407 (1): 103–16. doi:10.1016/S0003-9861(02)00464-2. PMID 12392720.
- Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, Doi T, Shimotohno K, Harada T, Nishida E, Hayashi H, Sugano S (May 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 (Sep 2003). "PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway". The Journal of Biological Chemistry. 278 (39): 36989–92. doi:10.1074/jbc.C300313200. PMID 12912994.
- Huang Q, Yang J, Lin Y, Walker C, Cheng J, Liu ZG, Su B (Jan 2004). "Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3". Nature Immunology. 5 (1): 98–103. doi:10.1038/ni1014. PMID 14661019. S2CID 24806598.
- Samanta AK, Huang HJ, Bast RC, Liao WS (Feb 2004). "Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappaB". The Journal of Biological Chemistry. 279 (9): 7576–83. doi:10.1074/jbc.M311659200. PMID 14662759.
- Stevens MV, Broka DM, Parker P, Rogowitz E, Vaillancourt RR, Camenisch TD (Dec 2008). "MEKK3 initiates transforming growth factor beta 2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis". Circulation Research. 103 (12): 1430–40. doi:10.1161/CIRCRESAHA.108.180752. PMC 2728220. PMID 19008476.
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