Biology:MAP3K1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) is a signal transduction enzyme that in humans is encoded by the autosomal MAP3K1 gene.[1][2]

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).[3][4] Mitogen-activated protein kinase kinases (MAP2Ks) are substrates for direct phosphorylation by the MAP3K1 protein kinase.[5][6] The MAP3K1 kinase domain may also be a modest activator of IκB kinase activation.[7] 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.[8] Genetics has revealed that MAP3K1 is important in: embryonic development, tumorigenesis, cell growth, cell migration, cytokine production, and humoral immunity.[4] MAP3K1 mutants were identified in breast cancer by GWAS.[9][10]

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.[11][12][13][14]

Genetic analyses in murine and avian models

MAP3K1 is highly conserved in Euteleostomi.[15] 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.[16] 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 [17][18][19][20]
Deletion kinase domain Mus musculus Transgenic mouse and embryonic stem cells [21][22][23][24][25]
Point mutations in Map3k1 exon 7 encoding E3 ubiquitin ligase Mus musculus Transgenic mouse and embryonic stem cells [8]
T cell-specific deletion generated by Lck promoter-driven Cre Mus musculus Transgenic mouse [26]
Deletion carboxyl-terminus Gallus gallus domesticus Lymphoblast cell line [27][28]

Mechanism of MAPK activation by MAP3K1

MAP3K1 contains multiple amino acid sites that are phosphorylated and ubiquitinated.[29] Early biochemical analysis demonstrated that triple co-expression of MAP3K1, MAP2K and MAPK in bacterial cells was sufficient for the activation of MAPK.[30] 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.[31][32][33][34] 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.[35][36] Genetic analysis has demonstrated that the E3 Ub ligase  and the kinase domains of MAP3K1 are required for MAPK activation.[28][37][38]

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.[39] MAP3K1 has been associated with several diseases in non-syngeneic human populations,[40] including: breast cancer,[41] adenocarcinoma of the prostate,[42] sarcomatoid hepatocellular carcinoma,[43] acute respiratory distress syndrome,[44] Langerhans cell histiocytosis,[45] and 46,XY disorders of sex development.[46] E6201 is an enzyme inhibitor of MAP3K1 that shows cross-specificity with MAP2K1.[47]

Interaction partners

MAP3K1 has been shown to interact with a number of proteins,[40] including:

References

  1. ↑ "Mapping of the MEK kinase gene (Mekk) to mouse chromosome 13 and human chromosome 5". Mammalian Genome 6 (11): 782–783. November 1995. doi:10.1007/BF00539003. PMID 8597633. 
  2. ↑ "Entrez Gene: MAP3K1 mitogen-activated protein kinase kinase kinase 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4214. 
  3. ↑ "The TAO of MEKK". Frontiers in Bioscience 3 (4): D1181–D1186. November 1998. doi:10.2741/a354. PMID 9820741. 
  4. ↑ 4.0 4.1 "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): 540–548. April 2015. doi:10.1038/cdd.2014.239. PMID 25613373. 
  5. ↑ "Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK". Science 266 (5191): 1719–1723. December 1994. doi:10.1126/science.7992057. PMID 7992057. Bibcode: 1994Sci...266.1719M. 
  6. ↑ "From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance". IUBMB Life 57 (4–5): 283–295. 2005. doi:10.1080/15216540500097111. PMID 16036612. 
  7. ↑ "JNK or IKK, AP-1 or NF-kappaB, which are the targets for MEK kinase 1 action?". Proceedings of the National Academy of Sciences of the United States of America 95 (16): 9067–9069. August 1998. doi:10.1073/pnas.95.16.9067. PMID 9689033. Bibcode: 1998PNAS...95.9067K. 
  8. ↑ 8.0 8.1 "The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines". The EMBO Journal 33 (21): 2581–2596. November 2014. doi:10.15252/embj.201488351. PMID 25260751. 
  9. ↑ "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. January 2015. doi:10.1016/j.ajhg.2014.11.009. PMID 25529635. 
  10. ↑ "Genome-wide association study identifies novel breast cancer susceptibility loci". Nature 447 (7148): 1087–1093. June 2007. doi:10.1038/nature05887. PMID 17529967. Bibcode: 2007Natur.447.1087E. 
  11. ↑ "Q13233 (M3K1_HUMAN)". Swiss Model. Swiss Institute of Bioinformatics. https://swissmodel.expasy.org/repository/uniprot/Q13233?csm=5CB78242295411D9. 
  12. ↑ "Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1". Nature 372 (6508): 798–800. 22–29 December 1994. doi:10.1038/372798a0. PMID 7997270. Bibcode: 1994Natur.372..798Y. 
  13. ↑ "The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2". Molecular Cell 9 (5): 945–956. May 2002. doi:10.1016/s1097-2765(02)00519-1. PMID 12049732. 
  14. ↑ "A cryptic tubulin-binding domain links MEKK1 to curved tubulin protomers". Proceedings of the National Academy of Sciences of the United States of America 117 (35): 21308–21318. September 2020. doi:10.1073/pnas.2006429117. PMID 32817551. Bibcode: 2020PNAS..11721308F. 
  15. ↑ "HomoloGene - NCBI". https://www.ncbi.nlm.nih.gov/homologene/8056. 
  16. ↑ "The open-eyelid mutation, lidgap-Gates, is an eight-exon deletion in the mouse Map3k1 gene". Genomics 85 (1): 139–142. January 2005. doi:10.1016/j.ygeno.2004.10.002. PMID 15607429. 
  17. ↑ "Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption". Science 282 (5395): 1911–1914. December 1998. doi:10.1126/science.282.5395.1911. PMID 9836645. Bibcode: 1998Sci...282.1911Y. 
  18. ↑ "MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-kappa B activation". Proceedings of the National Academy of Sciences of the United States of America 97 (13): 7272–7277. June 2000. doi:10.1073/pnas.130176697. PMID 10852963. Bibcode: 2000PNAS...97.7272Y. 
  19. ↑ "MEK kinase 1 (MEKK1) transduces c-Jun NH2-terminal kinase activation in response to changes in the microtubule cytoskeleton". The Journal of Biological Chemistry 274 (18): 12605–12610. April 1999. doi:10.1074/jbc.274.18.12605. PMID 10212239. 
  20. ↑ "MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes". Proceedings of the National Academy of Sciences of the United States of America 96 (26): 15127–15132. December 1999. doi:10.1073/pnas.96.26.15127. PMID 10611349. Bibcode: 1999PNAS...9615127M. 
  21. ↑ "A role for MEK kinase 1 in TGF-beta/activin-induced epithelium movement and embryonic eyelid closure". The EMBO Journal 22 (17): 4443–4454. September 2003. doi:10.1093/emboj/cdg440. PMID 12941696. 
  22. ↑ "Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch". Science 306 (5694): 271–275. October 2004. doi:10.1126/science.1099414. PMID 15358865. Bibcode: 2004Sci...306..271G. 
  23. ↑ "Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production". Nature Immunology 8 (1): 57–63. January 2007. doi:10.1038/ni1421. PMID 17143273. 
  24. ↑ "MEK kinase 1 activity is required for definitive erythropoiesis in the mouse fetal liver". Blood 106 (10): 3396–3404. November 2005. doi:10.1182/blood-2005-04-1739. PMID 16081685. 
  25. ↑ "MEK kinase 1 is a negative regulator of virus-specific CD8(+) T cells". European Journal of Immunology 36 (8): 2076–2084. August 2006. doi:10.1002/eji.200535163. PMID 16761309. 
  26. ↑ "T-Cell-Specific Deletion of Map3k1 Reveals the Critical Role for Mekk1 and Jnks in Cdkn1b-Dependent Proliferative Expansion". Cell Reports 14 (3): 449–457. January 2016. doi:10.1016/j.celrep.2015.12.047. PMID 26774476. 
  27. ↑ "MEKK1 is essential for DT40 cell apoptosis in response to microtubule disruption". Molecular and Cellular Biology 21 (21): 7183–7190. November 2001. doi:10.1128/MCB.21.21.7183-7190.2001. PMID 11585901. 
  28. ↑ 28.0 28.1 "Apoptosis induced by cytoskeletal disruption requires distinct domains of MEKK1". PLOS ONE 6 (2): e17310. February 2011. doi:10.1371/journal.pone.0017310. PMID 21364884. Bibcode: 2011PLoSO...617310T. 
  29. ↑ "MEKK1 (human)". https://www.phosphosite.org/proteinAction?id=1736&showAllSites=true. 
  30. ↑ "Reconstitution of mitogen-activated protein kinase phosphorylation cascades in bacteria. Efficient synthesis of active protein kinases". The Journal of Biological Chemistry 272 (17): 11057–11062. April 1997. doi:10.1074/jbc.272.17.11057. PMID 9110999. 
  31. ↑ "TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival". Immunity 7 (5): 703–713. November 1997. doi:10.1016/s1074-7613(00)80390-8. PMID 9390693. 
  32. ↑ "Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling". Nature Immunology 7 (9): 962–970. September 2006. doi:10.1038/ni1367. PMID 16862162. 
  33. ↑ "Essential function for the kinase TAK1 in innate and adaptive immune responses". Nature Immunology 6 (11): 1087–1095. November 2005. doi:10.1038/ni1255. PMID 16186825. 
  34. ↑ "Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production". Nature Immunology 8 (1): 57–63. January 2007. doi:10.1038/ni1421. PMID 17143273. 
  35. ↑ "Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex". Science 321 (5889): 663–668. August 2008. doi:10.1126/science.1157340. PMID 18635759. Bibcode: 2008Sci...321..663M. 
  36. ↑ "TNFR signaling: ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes". Immunological Reviews 228 (1): 225–240. March 2009. doi:10.1111/j.1600-065X.2008.00755.x. PMID 19290931. 
  37. ↑ 37.0 37.1 "The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines". The EMBO Journal 33 (21): 2581–2596. November 2014. doi:10.15252/embj.201488351. PMID 25260751. 
  38. ↑ "MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration". Proceedings of the National Academy of Sciences of the United States of America 97 (10): 5243–5248. May 2000. doi:10.1073/pnas.97.10.5243. PMID 10805784. Bibcode: 2000PNAS...97.5243X. 
  39. ↑ "MAP3K1 - My Cancer Genome". https://www.mycancergenome.org/content/gene/map3k1/. 
  40. ↑ 40.0 40.1 "MAP3K1 mitogen-activated protein kinase kinase kinase 1 [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/4214#. 
  41. ↑ "The landscape of cancer genes and mutational processes in breast cancer". Nature 486 (7403): 400–404. May 2012. doi:10.1038/nature11017. PMID 22722201. Bibcode: 2012Natur.486..400.. 
  42. ↑ "First case of ductal adenocarcinoma of the prostate with MAP3K1 homozygous deletion". IJU Case Reports 4 (3): 176–179. May 2021. doi:10.1002/iju5.12274. PMID 33977253. 
  43. ↑ "Sarcomatoid hepatocellular carcinoma: From clinical features to cancer genome". Cancer Medicine 10 (18): 6227–6238. September 2021. doi:10.1002/cam4.4162. PMID 34331411. 
  44. ↑ "Genetic Variation in MAP3K1 Associates with Ventilator-Free Days in Acute Respiratory Distress Syndrome". American Journal of Respiratory Cell and Molecular Biology 58 (1): 117–125. January 2018. doi:10.1165/rcmb.2017-0030OC. PMID 28858533. 
  45. ↑ "MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis". Genes, Chromosomes & Cancer 54 (6): 361–368. June 2015. doi:10.1002/gcc.22247. PMID 25899310. 
  46. ↑ "Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination". American Journal of Human Genetics 87 (6): 898–904. December 2010. doi:10.1016/j.ajhg.2010.11.003. PMID 21129722. 
  47. ↑ "E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8, 9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione], a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-1 and MEK kinase-1: in vitro characterization of its anti-inflammatory and antihyperproliferative activities". The Journal of Pharmacology and Experimental Therapeutics 331 (2): 485–495. November 2009. doi:10.1124/jpet.109.156554. PMID 19684251. 
  48. ↑ "Casein kinase I and casein kinase II differentially regulate axin function in Wnt and JNK pathways". The Journal of Biological Chemistry 277 (20): 17706–17712. May 2002. doi:10.1074/jbc.M111982200. PMID 11884395. 
  49. ↑ "Dimerization choices control the ability of axin and dishevelled to activate c-Jun N-terminal kinase/stress-activated protein kinase". The Journal of Biological Chemistry 275 (32): 25008–25014. August 2000. doi:10.1074/jbc.M002491200. PMID 10829020. 
  50. ↑ "MEKK1 binds raf-1 and the ERK2 cascade components". The Journal of Biological Chemistry 275 (51): 40120–40127. December 2000. doi:10.1074/jbc.M005926200. PMID 10969079. 
  51. ↑ "Grb2 interaction with MEK-kinase 1 is involved in regulation of Jun-kinase activities in response to epidermal growth factor". The Journal of Biological Chemistry 273 (38): 24301–24304. September 1998. doi:10.1074/jbc.273.38.24301. PMID 9733714. 
  52. ↑ "MEKK1 binds directly to the c-Jun N-terminal kinases/stress-activated protein kinases". The Journal of Biological Chemistry 272 (51): 32056–32060. December 1997. doi:10.1074/jbc.272.51.32056. PMID 9405400. 
  53. ↑ "Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain". Genes & Development 13 (10): 1297–1308. May 1999. doi:10.1101/gad.13.10.1297. PMID 10346818. 
  54. ↑ "hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity". FEBS Letters 425 (3): 431–435. April 1998. doi:10.1016/s0014-5793(98)00287-7. PMID 9563508. 
  55. ↑ "RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity". The Journal of Biological Chemistry 279 (3): 1872–1877. January 2004. doi:10.1074/jbc.M309525200. PMID 14581471. 
  56. ↑ "MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42". The EMBO Journal 16 (16): 4961–4972. August 1997. doi:10.1093/emboj/16.16.4961. PMID 9305638. 
  57. ↑ "p115 Rho GTPase activating protein interacts with MEKK1". Journal of Cellular Physiology 192 (2): 200–208. August 2002. doi:10.1002/jcp.10125. PMID 12115726. 
  58. ↑ "JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension". Genes & Development 12 (21): 3369–3381. November 1998. doi:10.1101/gad.12.21.3369. PMID 9808624. 
  59. ↑ "MEK kinase 1 interacts with focal adhesion kinase and regulates insulin receptor substrate-1 expression". The Journal of Biological Chemistry 278 (6): 3846–3851. February 2003. doi:10.1074/jbc.M206087200. PMID 12458213. 

Further reading

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



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