MAP3K1

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is an enzyme that in humans is encoded by the MAP3K1 gene.[5][6]

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
Gene location (Human)
Chr.Chromosome 5 (human)[1]
Band5q11.2Start56,815,549 bp[1]
End56,896,152 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

4214

26401

Ensembl

ENSG00000095015

ENSMUSG00000021754

UniProt

Q13233

P53349

RefSeq (mRNA)

NM_005921

NM_011945

RefSeq (protein)

NP_005912

n/a

Location (UCSC)Chr 5: 56.82 – 56.9 MbChr 13: 111.75 – 111.81 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

MAP3K1 (or MEKK1) is a serine/threonine kinase that performs a pivotal role in a network of phosphorylating kinase 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] Mouse genetics has revealed that MAP3K1 is important in: embryonic development, tumorigenesis, cell growth, cell migration, cytokine production, and humoral immunity.[8] MAP3K1 has been identified by GWAS in breast cancer [11][12]

Structure

MAP3K1 contains a protein kinase domain as well as PHD finger (which has a RING finger domain-like structure) and scaffold protein regions that mediate protein–protein interactions.[13][14][15]

Genetic analyses in murine and avian models

MAP3K1 is highly conserved in Euteleostomi.[16] The recessive lidgap-Gates mutation (first 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.[17] MAP3K1 has been analysed genetically by targeted mutagenesis using transgenic mice, embryonic stem cells, and the DT40 cell line to identify genetic traits.

Map3k1 mutantSpeciesGenetic modelReferences
Deletion amino-terminusMus musculusTransgenic mouse and embryonic stem cells[18][19]
Deletion kinase domainMus musculusTransgenic mouse and embryonic stem cells[20][21][22]
Point mutations PHD fingerMus musculusTransgenic mouse and embryonic stem cells[23]
T cell-specific deletionMus musculusTransgenic mouse[24]
Deletion carboxyl-terminusGallus gallus domesticusLymphoblast cell line[25][26]

Activation and deactivation

MAP3K1 contains multiple sites that are phosphorylated and ubiquitinated.[27] Cytokine signaling through MAP3K1 utilises two-stage cell signaling to recruit the signal transduction mechanism to cytokine receptors and then release these components from the cellular membrane.[28][29]

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 mutated in 3.05% of all human cancers.[30] MAP3K1 is a breast cancer susceptibility allele,[31] acute respiratory distress syndrome associated allele,[32] Langerhans cell histiocytosis gene,[33] and 46,XY disorders of sex development linked gene.[34] E6201 is an enzyme inhibitor of MAP3K1 that shows cross-specificity with MAP2K1.[35]

Interaction partners

MAP3K1 has been shown to interact with a number of proteins,[36] including:

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gollark: How horrible.

References
  1. GRCh38: Ensembl release 89: ENSG00000095015 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000021754 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. "Entrez Gene: MAP3K1 mitogen-activated protein kinase kinase kinase 1".
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  8. Suddason T, Gallagher E (April 2015). "A RING to rule them all? Insights into the Map3k1 PHD motif provide a new mechanistic understanding into the diverse roles of Map3k1". Cell Death and Differentiation. 22 (4): 540–8. doi:10.1038/cdd.2014.239. PMC 4356348. PMID 25613373.
  9. Minden A, Lin A, McMahon M, Lange-Carter C, Dérijard B, Davis RJ, et al. (December 1994). "Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK". Science. 266 (5191): 1719–23. Bibcode:1994Sci...266.1719M. doi:10.1126/science.7992057. PMID 7992057.
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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.
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