MAP3K1
Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is a signal transduction enzyme that in humans is encoded by the autosomal "MAP3K1" gene. 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). Mitogen-activated protein kinase kinases (MAP2Ks) are substrates for direct phosphorylation by the MAP3K1 protein kinase. 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. Genetics has revealed that "MAP3K1" is important in: embryonic development, tumorigenesis, cell growth, cell migration, cytokine production, and humoral immunity. "MAP3K1" mutants were identified in breast cancer by GWAS. 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. Genetic analyses in murine and  avian models. MAP3K1 is highly conserved in Euteleostomi. 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) "MAP3K1" homolog ("Map3k1") and also co-maps to distal Chromosome 13. "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. Mechanism of MAPK activation by MAP3K1. MAP3K1 contains multiple amino  acid sites that are phosphorylated and ubiquitinated. 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. 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. Genetic analysis has demonstrated that the E3 Ub ligase  and the kinase domains of MAP3K1 are required for MAPK activation. Disease and therapeutic targeting. "MAP3K1" is a biomarker mutated in 3.24 % of all human cancers. "MAP3K1" has been associated with several diseases in non-syngeneic human populations, including: breast cancer, adenocarcinoma of the prostate, sarcomatoid hepatocellular carcinoma, acute respiratory distress syndrome, Langerhans cell histiocytosis, and 46,XY disorders of sex development. E6201 is an enzyme inhibitor of MAP3K1 that shows cross-specificity with MAP2K1. Interaction partners. MAP3K1 has been shown to interact with a number of proteins, including: