|Mitogen-activated protein kinase kinase kinase 3|
PDB rendering based on 2c60.
|Symbols||; MAPKKK3; MEKK3|
|External IDs||IUPHAR: ChEMBL: GeneCards:|
|RNA expression pattern|
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 (NFKB)-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.
MAP3K3 in cancer
Many studies have described the association of MAP3K3 (or MEKK3) 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.
Normal endothelial cells, but deficient in MEKK3, have reduced cell proliferation and increased apoptosis. MEKK3-deficient tumors, on the other hand, can grow in the same rate as regular tumors, also producing comparable levels of VEGF and inducing angiogenesis comparably to wild-type tumors. While these results show that MEKK3 is important for normal endothelial cells, MEKK3 may not be necessary for tumor growth and angiogenesis.
MEKK3 expression level is also significantly higher in cervical cancer in comparison with chronic cervicitis and CIN (cervical intraepithelial neoplasia). This high expression correlates with the also high levels of survivin (apoptosis inhibitor), and they both may associate with cervical cancer development and prognosis. Cao et al. suggest a targeted therapy of MEKK3 together with a therapy that promotes apoptosis as a possible new strategy for treatment of chemotherapeutic-resistant tumors.
Similarly, significantly higher levels of MEKK3 was found as well in esophageal dysplasia and esophageal squamous cell carcinoma (ESCC) when compared to normal esophageal tissue. MEKK3 seems to accumulate even more in ESCC than esophageal dysplasia, which also correlates with poor prognosis of ESCC. Therefore, MEKK3 can be studied for its possible role as an early biomarker of esophageal tumorigenesis.
From all these studies, MEKK3 has become a valuable target for the development of new cancer therapies and diagnosis/prognosis tools.
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