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]
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:
A mitogen-activated protein kinase is a type of protein kinase that is specific to the amino acids serine and threonine. MAPKs are involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.
Mitogen Activated Protein (MAP) kinase kinase kinase is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
In molecular biology, extracellular signal-regulated kinases (ERKs) or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Many different stimuli, including growth factors, cytokines, virus infection, ligands for heterotrimeric G protein-coupled receptors, transforming agents, and carcinogens, activate the ERK pathway.
Mitogen-activated protein kinase kinase is a dual-specificity kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).
RAF kinases are a family of three serine/threonine-specific protein kinases that are related to retroviral oncogenes. The mouse sarcoma virus 3611 contains a RAF kinase-related oncogene that enhances fibrosarcoma induction. RAF is an acronym for Rapidly Accelerated Fibrosarcoma.
ITCH is a HECT domain E3 ubiquitin ligase that is ablated in non-agouti-lethal 18H mice. Itchy mice develop a severe immunological phenotype after birth that includes hyperplasia of lymphoid and hematopoietic cells, and stomach and lung inflammation. In humans ITCH deficiency causes altered physical growth, craniofacial morphology defects, defective muscle development, and aberrant immune system function. ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated.
Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.
Mitogen-activated protein kinase 8 is a ubiquitous enzyme that in humans is encoded by the MAPK8 gene.
Dual specificity mitogen-activated protein kinase kinase 1 is an enzyme that in humans is encoded by the MAP2K1 gene.
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the MAP3K7 gene.
Dual-specificity mitogen-activated protein kinase kinase 4 is an enzyme that in humans is encoded by the MAP2K4 gene.
Dual specificity mitogen-activated protein kinase kinase 3 is an enzyme that in humans is encoded by the MAP2K3 gene.
C-jun-amino-terminal kinase-interacting protein 1 is an enzyme that in humans is encoded by the MAPK8IP1 gene.
Dual specificity mitogen-activated protein kinase kinase 7, also known as MAP kinase kinase 7 or MKK7, is an enzyme that in humans is encoded by the MAP2K7 gene. This protein is a member of the mitogen-activated protein kinase kinase family. The MKK7 protein exists as six different isoforms with three possible N-termini and two possible C-termini.
Ribosomal protein S6 kinase alpha-5 is an enzyme that in humans is encoded by the RPS6KA5 gene. This kinase, together with RPS6KA4, are thought to mediate the phosphorylation of histone H3, linked to the expression of immediate early genes.
Mitogen-activated protein kinase kinase kinase 4 is an enzyme that in humans is encoded by the MAP3K4 gene.
Mitogen-Activated Protein Kinase Kinase Kinase 2 also known as MEKK2 is an enzyme that in humans is encoded by the MAP3K2 gene.
C-jun-amino-terminal kinase-interacting protein 2 is a protein or the name of the gene that encodes it. The gene is also known as Islet-Brain-2 (IB2).
Candidalysin is a cytolytic 31-amino acid α-helical amphipathic peptide toxin secreted by the opportunistic pathogen Candida albicans. This toxin is a fungal example of a classical virulence factor. Hyphal morphogenesis in C. albicans is associated with damage to host epithelial cells; during this process Candidalysin is released and intercalates in host membranes. Candidalysin promotes damage of oral epithelial cells and induces lactate dehydrogenase release and calcium ion influx. It is unique in the fact that it is the first peptide toxin to be identified in any human fungal pathogen.
