MAP3K1
Identifiers
AliasesMAP3K1, MAPKKK1, MEKK, MEKK 1, MEKK1, SRXY6, mitogen-activated protein kinase kinase kinase 1
External IDsOMIM: 600982 MGI: 1346872 HomoloGene: 8056 GeneCards: MAP3K1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005921

NM_011945

RefSeq (protein)

NP_005912

n/a

Location (UCSC)Chr 5: 56.82 – 56.9 MbChr 13: 111.88 – 111.95 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

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).[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]

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.[15][16][17][18]

Genetic analyses in murine and avian models

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]

Mechanism of MAPK activation by MAP3K1

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 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.
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.

Cancers, other diseases and therapeutic targeting

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]

Interaction partners

MAP3K1 has been shown to interact with a number of proteins,[44] including:

References

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Further reading

  • Lin, A (2006). "The JNK Signaling Pathway (Molecular Biology Intelligence Unit)". Landes Bioscience. 1: 1–97. ISBN 978-1587061202.