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]
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]
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]
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.
Map3k1 mutant | Species | Genetic model | References |
---|---|---|---|
Deletion of 132 codons in Map3k1 exon 1 | Mus musculus | Transgenic mouse and embryonic stem cells | [21][22][23][24] |
Deletion kinase domain | Mus musculus | Transgenic mouse and embryonic stem cells | [25][26][27][28][29] |
Point mutations in Map3k1 exon 7 encoding E3 ubiquitin ligase | Mus musculus | Transgenic mouse and embryonic stem cells | [12] |
T cell-specific deletion generated by Lck promoter-driven Cre | Mus musculus | Transgenic mouse | [30] |
Deletion carboxyl-terminus | Gallus gallus domesticus | Lymphoblast cell line | [31][32] |
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 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]
MAP3K1 has been shown to interact with a number of proteins,[44] including: