Mitogen-activated protein kinase kinase kinase 3 is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that in humans is encoded by the ''MAP3K3''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
,
which is located on the long arm of chromosome 17 (17q23.3).
[MAP3K3 in GeneCards – The Human Gene Compendium. https://www.genecards.org/cgi-bin/carddisp.pl?gene=MAP3K3]
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
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with
QSTM1/p62:
*
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
,
AKT.
*
GAB1
GRB2-associated-binding protein 1 is a protein that in humans is encoded by the ''GAB1'' gene.
Function
The protein encoded by this gene is a member of the IRS1-like multisubstrate docking protein family. The encoded protein is an important m ...
,
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MAP2K5
Dual specificity mitogen-activated protein kinase kinase 5 is an enzyme that in humans is encoded by the ''MAP2K5'' gene.
Function
The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase famil ...
,
and
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YWHAE
14-3-3 protein epsilon is a protein that in humans is encoded by the ''YWHAE'' gene.
Function
This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This hi ...
.
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
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
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
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
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
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
. Knocking down BRCA1 resulted in inhibited MEKK3 kinase activity. The drug
paclitaxel
Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical ca ...
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.
References
Further reading
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