Biology:MAP3K3

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

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

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. 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. MEKK3 regulates the p38, JNK and ERK1/2 pathways.

Interactions

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

• BRCA1, AKT.
• GAB1,
• MAP2K5, and
• YWHAE.

MAP3K3 in cancer

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

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.

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.

Further reading

• "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. Jan 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
• "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. Sep 1996. doi:10.1101/gr.6.9.791. PMID 8889548. 
• "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. Oct 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
• "14-3-3 proteins interact with specific MEK kinases". The Journal of Biological Chemistry 273 (6): 3476–83. Feb 1998. doi:10.1074/jbc.273.6.3476. PMID 9452471. 
• "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. Dec 1999. doi:10.1074/jbc.274.51.36035. PMID 10593883. 
• "Mekk3 is essential for early embryonic cardiovascular development". Nature Genetics 24 (3): 309–13. Mar 2000. doi:10.1038/73550. PMID 10700190. 
• "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". The Journal of Biological Chemistry 276 (7): 5093–100. Feb 2001. doi:10.1074/jbc.M003719200. PMID 11073940. 
• "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. Nov 2000. doi:10.1101/gr.143000. PMID 11076863. 
• "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. Mar 2001. doi:10.1101/gr.GR1547R. PMID 11230166. 
• "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports 1 (3): 287–92. Sep 2000. doi:10.1093/embo-reports/kvd058. PMID 11256614. 
• "The essential role of MEKK3 in TNF-induced NF-kappaB activation". Nature Immunology 2 (7): 620–4. Jul 2001. doi:10.1038/89769. PMID 11429546. 
• "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. Jun 2002. doi:10.1161/01.RES.0000021127.83364.7D. PMID 12065326. 
• "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. Oct 2002. doi:10.1073/pnas.232310199. PMID 12391307. Bibcode: 2002PNAS...9914189L. 
• "Phosphorylation of the stress-activated protein kinase, MEKK3, at serine 166". Archives of Biochemistry and Biophysics 407 (1): 103–16. Nov 2002. doi:10.1016/S0003-9861(02)00464-2. PMID 12392720. 
• "Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways". Oncogene 22 (21): 3307–18. May 2003. doi:10.1038/sj.onc.1206406. PMID 12761501. 
• "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. Sep 2003. doi:10.1074/jbc.C300313200. PMID 12912994. 
• "Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3". Nature Immunology 5 (1): 98–103. Jan 2004. doi:10.1038/ni1014. PMID 14661019. 
• "Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappaB". The Journal of Biological Chemistry 279 (9): 7576–83. Feb 2004. doi:10.1074/jbc.M311659200. PMID 14662759. 
• "MEKK3 initiates transforming growth factor beta 2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis". Circulation Research 103 (12): 1430–40. Dec 2008. doi:10.1161/CIRCRESAHA.108.180752. PMID 19008476.