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:

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.
  5. Vinik BS, Kay ES, Fiedorek FT (November 1995). "Mapping of the MEK kinase gene (Mekk) to mouse chromosome 13 and human chromosome 5". Mammalian Genome. 6 (11): 782–3. doi:10.1007/BF00539003. PMID 8597633.
  6. "Entrez Gene: MAP3K1 mitogen-activated protein kinase kinase kinase 1".
  7. Schlesinger TK, Fanger GR, Yujiri T, Johnson GL (November 1998). "The TAO of MEKK". Frontiers in Bioscience. 3 (4): D1181–6. doi:10.2741/a354. PMID 9820741.
  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.
  10. Karin M, Gallagher E (2005). "From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance". IUBMB Life. 57 (4–5): 283–95. doi:10.1080/15216540500097111. PMID 16036612.
  11. Glubb DM, Maranian MJ, Michailidou K, Pooley KA, Meyer KB, Kar S, et al. (January 2015). "Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1". American Journal of Human Genetics. 96 (1): 5–20. doi:10.1016/j.ajhg.2014.11.009. PMC 4289692. PMID 25529635.
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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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