MAP3K3

Main article: MAP kinase kinase kinase

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).

MAP3K3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2C60, 2JRH, 2PPH, 4Y5O, 4YL6, 2O2V
Identifiers
Aliases	MAP3K3, MAPKKK3, MEKK3, mitogen-activated protein kinase kinase kinase 3
External IDs	OMIM: 602539; MGI: 1346874; HomoloGene: 69110; GeneCards: MAP3K3; OMA:MAP3K3 - orthologs
Gene location (Human) Chr. Chromosome 17 (human) Band 17q23.3 Start 63,622,415 bp End 63,696,305 bp
Gene location (Mouse) Chr. Chromosome 11 (mouse) Band 11|11 E1 Start 105,975,439 bp End 106,046,272 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte granulocyte blood gastric mucosa apex of heart right lung right coronary artery popliteal artery tibial arteries spleen Top expressed in granulocyte internal carotid artery ascending aorta aortic valve external carotid artery fossa Rostral migratory stream condyle tunica media of zone of aorta blood More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ATP binding protein kinase activity protein binding MAP kinase kinase kinase activity kinase activity metal ion binding nucleotide binding transferase activity protein serine/threonine kinase activity Cellular component cytosol cytoplasm Biological process intracellular signal transduction protein phosphorylation positive regulation of p38MAPK cascade protein autophosphorylation blood vessel development phosphorylation positive regulation of I-kappaB kinase/NF-kappaB signaling regulation of mitotic cell cycle stress-activated protein kinase signaling cascade activation of protein kinase activity regulation of apoptotic process MAPK cascade interleukin-1-mediated signaling pathway positive regulation of cell proliferation in bone marrow positive regulation of cell migration involved in sprouting angiogenesis negative regulation of cellular senescence signal transduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4215 26406 Ensembl ENSG00000198909 ENSMUSG00000020700 UniProt Q99759 Q61084 RefSeq (mRNA) NM_002401 NM_203351 NM_001330431 NM_001363768 NM_011947 RefSeq (protein) NP_001317360 NP_002392 NP_976226 NP_001350697 NP_036077 Location (UCSC) Chr 17: 63.62 – 63.7 Mb Chr 11: 105.98 – 106.05 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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

• 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.