MAP3K3

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.{{cite journal | vauthors = Craig EA, Stevens MV, Vaillancourt RR et al | year = 2008 | title = MAP3Ks as central regulators of cell fate during development | journal = Developmental Dynamics | volume = 237 | issue = 11| pages = 3102–14 | doi=10.1002/dvdy.21750 | pmid=18855897| s2cid = 876964 | doi-access = free }} 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.{{cite web | title = Entrez Gene: MAP3K3 mitogen-activated protein kinase kinase kinase 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4215}} MEKK3 regulates the p38, JNK and ERK1/2 pathways.

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

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• BRCA1,{{cite journal | vauthors = 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 | title = BRCA1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3 | journal = Cancer Research | volume = 64 | issue = 12 | pages = 4148–54 | date = Jun 2004 | pmid = 15205325 | doi = 10.1158/0008-5472.CAN-03-4080 | doi-access = free }} AKT.
• GAB1,{{cite journal | vauthors = Che W, Lerner-Marmarosh N, Huang Q, Osawa M, Ohta S, Yoshizumi M, Glassman M, Lee JD, Yan C, Berk BC, Abe J | title = 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 | journal = Circulation Research | volume = 90 | issue = 11 | pages = 1222–30 | date = Jun 2002 | pmid = 12065326 | doi = 10.1161/01.RES.0000021127.83364.7D| doi-access = free }}
• MAP2K5,{{cite journal | vauthors = Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, Gelfand EW, Johnson GL | title = MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway | journal = The Journal of Biological Chemistry | volume = 276 | issue = 7 | pages = 5093–100 | date = Feb 2001 | pmid = 11073940 | doi = 10.1074/jbc.M003719200 | doi-access = free }}{{cite journal | vauthors = 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 | title = A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway | journal = Nature Cell Biology | volume = 6 | issue = 2 | pages = 97–105 | date = Feb 2004 | pmid = 14743216 | doi = 10.1038/ncb1086 | s2cid = 11683986 }} and
• YWHAE.{{cite journal | vauthors = Fanger GR, Widmann C, Porter AC, Sather S, Johnson GL, Vaillancourt RR | title = 14-3-3 proteins interact with specific MEK kinases | journal = The Journal of Biological Chemistry | volume = 273 | issue = 6 | pages = 3476–83 | date = Feb 1998 | pmid = 9452471 | doi = 10.1074/jbc.273.6.3476| doi-access = free }}

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Two SNPs in the MAP3K3 gene were found as candidates for association with colon and rectal cancers.{{cite journal | vauthors = Slattery ML, Lundgreen A, Wolff RK | title = MAP kinase genes and colon and rectal cancer | journal = Carcinogenesis | volume = 33 | issue = 12 | pages = 2398–408 | year = 2012 | pmid = 23027623 | pmc = 3510742 | doi = 10.1093/carcin/bgs305 }}

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.{{cite journal | vauthors = Samanta AK, Huang HJ, Le XF, Mao W, Lu KH, Bast RC, Liao WS | title = MEKK3 expression correlates with nuclear factor kappa B activity and with expression of antiapoptotic genes in serous ovarian carcinoma | journal = Cancer | volume = 115 | issue = 17 | pages = 3897–908 | date = Sep 2009 | pmid = 19517469 | doi = 10.1002/cncr.24445 | pmc=3061353}}

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.

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Category:EC 2.7.11