Protein-coding gene in the species Homo sapiens
Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is a
signal transduction
enzyme that in humans is encoded by the
autosomal MAP3K1
gene .
[5]
[6]
Function
MAP3K1 (or MEKK1) is a serine/threonine
kinase and
ubiquitin ligase that performs a pivotal role in a network of
enzymes integrating cellular receptor responses to a number of mitogenic and metabolic stimuli, including:
TNF receptor superfamily (TNFRs),
T-cell receptor (TCR),
Epidermal growth factor receptor (EGFR), and
TGF beta receptor (TGFβR).
[7]
[8]
Mitogen-activated protein kinase kinases (MAP2Ks) are substrates for direct phosphorylation by the MAP3K1
protein kinase .
[9]
[10] The MAP3K1 kinase domain may also be a modest activator of IκB kinase activation.
[11] The MAP3K1 E3 ubiquitin ligase recruits a
ubiquitin-conjugating enzyme (including
UBE2D2 ,
UBE2D3 , and
UBE2N :
UBE2V1 ) that has been loaded with
ubiquitin , interacts with its substrates, and facilitates the transfer of ubiquitin from the ubiquitin-conjugating enzyme onto its substrates.
[12] Genetics has revealed that MAP3K1 is important in:
embryonic development ,
tumorigenesis ,
cell growth ,
cell migration ,
cytokine production, and
humoral immunity .
[8] MAP3K1 mutants were identified in
breast cancer by
GWAS .
[13]
[14]
Structure
MAP3K1 contains a
protein kinase domain ,
PHD finger (which has a
RING finger domain -like structure) that serves as an
E3 ubiquitin ligase , and
scaffold protein regions that mediate
protein–protein interactions .
[15]
[16]
[17]
[18]
Genetic analyses in murine and avian models
MAP3K1 is highly conserved in
Euteleostomi .
[19] The spontaneous
recessive lidgap-Gates mutation (deletion of Map3k1 exons 2–9, initially described in the 1960s) identified on the SELH/Bc mouse strain causes the same open-eyelids-at-birth mutational phenotype as the gene knockout mutations of the mouse (but not human) MAP3K1
homolog (Map3k1 ) and also co-maps to distal Chromosome 13.
[20] MAP3K1 was analysed genetically by targeted mutagenesis using
transgenic mice (
C57BL/6 and C57BL/6 × 129 backgrounds),
embryonic stem cells , and the DT40
cell line to identify
genetic traits .
Mechanism of MAPK activation by MAP3K1
MAP3K1 contains multiple
amino acid sites that are
phosphorylated and
ubiquitinated .
[33] Early biochemical analysis demonstrated that triple co-expression of MAP3K1, MAP2K and MAPK in bacterial cells was sufficient for the activation of MAPK.
[34] Later analysis of
syngenic mice that harbour mutations in TRAF2 , UBE2N , Map3k1 and Map3k7 identified critical regulators of cytokine-induced
MAPK signal transduction in B cells.
[35]
[36]
[37]
[38]
Cytokine signaling through MAP3K1 utilises two-stage
cell signaling to recruit the
signal transduction mechanism to
cytokine receptors and then release the signal transduction components, altered by
post-translational modification , from the
cellular membrane to activate MAPKs.
[39]
[40]
Genetic analysis has demonstrated that the E3 Ub ligase and the kinase domains of MAP3K1 are required for
MAPK activation.
[32]
[41]
[42]
MAP3K1 signal transduction . A . Cytokine receptor prior to ligation by cytokine. B . Recruitment of TRAFs 2, 3 and 6 to the cytokine receptor. C . Ubiquitination of TRAFs. Recruitment of MAP3K1 and MAP3K7 signaling modules to TRAFs and scaffolding. D . Degradation of canonical Ubiquitin-TRAF3 by the proteasome, release of non-canonical Ubiquitin-TRAF2 and -MAP3Ks into the cytoplasm, and activation of MAP2K signaling.
Cancers, other diseases and therapeutic targeting
MAP3K1 is a
biomarker mutated in 3.24% of all human cancers.
[43] MAP3K1 has been associated with several diseases in non-syngeneic human populations,
[44] including:
breast cancer ,
[45]
adenocarcinoma of the
prostate ,
[46] sarcomatoid
hepatocellular carcinoma ,
[47]
acute respiratory distress syndrome ,
[48]
Langerhans cell histiocytosis ,
[49] and 46,XY
disorders of sex development .
[50] E6201 is an
enzyme inhibitor of MAP3K1 that shows cross-specificity with
MAP2K1 .
[51]
Interaction partners
MAP3K1 has been shown to
interact with a number of proteins,
[44] including:
AXIN1 ,
[52]
[53]
C-Raf ,
MAP2K1 ,
MAPK1 ,
[54]
Grb2 ,
[55]
MAPK8 ,
[56]
TRAF2 ,
[57]
UBE2I .
[58]
TAB1 ,
TNIP1 ,
TNIP2 .
Signal transducing adaptor molecule ,
[41]
Transforming protein RhoA ,
[59]
RAC1 ,
CDC42 ,
[60]
ARHGAP4 ,
[61]
MAP2K4 ,
[62] and
PTK2 .
[63]
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Further reading
Lin, A (2006). "The JNK Signaling Pathway (Molecular Biology Intelligence Unit)". Landes Bioscience . 1 : 1–97.
ISBN
978-1587061202 .
Activity Regulation Classification Kinetics Types