Protein-coding gene in the species Homo sapiens
Mitogen -activated protein kinase kinase kinase 1 (MAP3K1)signal transduction enzyme that in humans is encoded by theautosomal MAP3K1 gene .[ 5] [ 6]
MAP3K1 (or MEKK1) is a serine/threoninekinase andubiquitin ligase that performs a pivotal role in a network ofenzymes 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), andTGF beta receptor (TGFβR).[ 7] [ 8] Mitogen-activated protein kinase kinases (MAP2Ks) are substrates for direct phosphorylation by the MAP3K1protein kinase .[ 9] [ 10] [ 11] ubiquitin-conjugating enzyme (includingUBE2D2 ,UBE2D3 , andUBE2N :UBE2V1 ) that has been loaded withubiquitin , interacts with its substrates, and facilitates the transfer of ubiquitin from the ubiquitin-conjugating enzyme onto its substrates.[ 12] MAP3K1 is important in:embryonic development ,tumorigenesis ,cell growth ,cell migration ,cytokine production, andhumoral immunity .[ 8] MAP3K1 mutants were identified inbreast cancer byGWAS .[ 13] [ 14]
MAP3K1 contains aprotein kinase domain ,PHD finger (which has aRING finger domain -like structure) that serves as anE3 ubiquitin ligase , andscaffold protein regions that mediateprotein–protein interactions .[ 15] [ 16] [ 17] [ 18]
Genetic analyses in murine and avian models [ edit ] MAP3K1 is highly conserved inEuteleostomi .[ 19] recessive lidgap-Gates mutation (deletion ofMap3k1 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 usingtransgenic mice (C57BL/6 and C57BL/6 × 129 backgrounds),embryonic stem cells , and the DT40cell line to identifygenetic traits .
Mechanism of MAPK activation by MAP3K1 [ edit ] MAP3K1 contains multipleamino acid sites that arephosphorylated andubiquitinated .[ 33] [ 34] syngenic mice that harbour mutations inTRAF2 ,UBE2N ,Map3k1 andMap3k7 identified critical regulators of cytokine-inducedMAPK signal transduction in B cells.[ 35] [ 36] [ 37] [ 38] Cytokine signaling through MAP3K1 utilises two-stagecell signaling to recruit thesignal transduction mechanism tocytokine receptors and then release the signal transduction components, altered bypost-translational modification , from thecellular membrane to activate MAPKs.[ 39] [ 40] Genetic analysis has demonstrated that the E3 Ub ligase and the kinase domains of MAP3K1 are required forMAPK 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.[ edit ] MAP3K1 is abiomarker mutated in 3.24% of all human cancers.[ 43] MAP3K1 has been associated with several diseases in non-syngeneic human populations,[ 44] breast cancer ,[ 45] adenocarcinoma of theprostate ,[ 46] hepatocellular carcinoma ,[ 47] acute respiratory distress syndrome ,[ 48] Langerhans cell histiocytosis ,[ 49] disorders of sex development .[ 50] enzyme inhibitor of MAP3K1 that shows cross-specificity withMAP2K1 .[ 51]
Interaction partners [ edit ] MAP3K1 has been shown tointeract with a number of proteins,[ 44]
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] PTK2 .[ 63]
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Activity Regulation Classification Kinetics Types
