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 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.[11] 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.[12][13]
MAP3K1 is highly conserved in Euteleostomi.[18] The spontaneous recessive lidgap-Gates mutation (deletion of Map3k1 exons 2–9, initially described in 1961) 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) MAP3K1homolog (Map3k1) and also co-maps to distal Chromosome 13.[19]MAP3K1 has been 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.
MAP3K1 contains multiple amino acid sites that are phosphorylated and ubiquitinated.[32] 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.[33][34][35][36]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.[37][38]Genetic analysis has demonstrated that the E3 Ub ligase and the kinase domains of MAP3K1 are required for MAPK activation.[31][39][40]
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.
Disease and therapeutic targeting[]
MAP3K1 is a biomarker mutated in 3.24% of all human cancers.[41]MAP3K1 has been associated with several diseases in non-syngeneic human populations,[42] including: breast cancer,[43]adenocarcinoma of the prostate,[44] sarcomatoid hepatocellular carcinoma,[45]acute respiratory distress syndrome,[46]Langerhans cell histiocytosis,[47] and 46,XY disorders of sex development.[48] E6201 is an enzyme inhibitor of MAP3K1 that shows cross-specificity with MAP2K1.[49]
Interaction partners[]
MAP3K1 has been shown to interact with a number of proteins,[42] including:
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