MAP3K3

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

Interactions
MAP3K3 has been shown to interact with [SQSTM1/p62], is_associated_with::MAP2K5, is_associated_with::YWHAE, is_associated_with::GAB1, is_associated_with::BRCA1, and AKT.

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 is_associated_with::kinase activities, which also relate to activation of is_associated_with::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-is_associated_with::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 is_associated_with::BRCA1. Knocking down BRCA1 resulted in inhibited MEKK3 kinase activity. The drug is_associated_with::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 is_associated_with::VEGF and inducing is_associated_with::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 is_associated_with::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.