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:

gollark: `free(dpwcnsa;lan)`
gollark: Until what, Protocol 126-T?
gollark: = apioautochorohypsohazard.
gollark: LyricLy = ur-apiovideohypnopalladoform.
gollark: Interesting.

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.
  12. Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, et al. (June 2007). "Genome-wide association study identifies novel breast cancer susceptibility loci". Nature. 447 (7148): 1087–93. Bibcode:2007Natur.447.1087E. doi:10.1038/nature05887. PMC 2714974. PMID 17529967.
  13. "Q13233 (M3K1_HUMAN)". Swiss Model. Swiss Institute of Bioinformatics.
  14. Yan M, Dai T, Deak JC, Kyriakis JM, Zon LI, Woodgett JR, Templeton DJ (22–29 December 1994). "Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1". Nature. 372 (6508): 798–800. Bibcode:1994Natur.372..798Y. doi:10.1038/372798a0. PMID 7997270.
  15. Lu Z, Xu S, Joazeiro C, Cobb MH, Hunter T (May 2002). "The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2". Molecular Cell. 9 (5): 945–56. doi:10.1016/s1097-2765(02)00519-1. PMID 12049732.
  16. "HomoloGene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-05-01.
  17. Juriloff DM, Harris MJ, Mah DG (January 2005). "The open-eyelid mutation, lidgap-Gates, is an eight-exon deletion in the mouse Map3k1 gene". Genomics. 85 (1): 139–42. doi:10.1016/j.ygeno.2004.10.002. PMID 15607429.
  18. Yujiri T, Sather S, Fanger GR, Johnson GL (December 1998). "Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption". Science. 282 (5395): 1911–4. Bibcode:1998Sci...282.1911Y. doi:10.1126/science.282.5395.1911. PMID 9836645.
  19. Yujiri T, Ware M, Widmann C, Oyer R, Russell D, Chan E, et al. (June 2000). "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): 7272–7. Bibcode:2000PNAS...97.7272Y. doi:10.1073/pnas.130176697. PMC 16535. PMID 10852963.
  20. Zhang L, Wang W, Hayashi Y, Jester JV, Birk DE, Gao M, et al. (September 2003). "A role for MEK kinase 1 in TGF-beta/activin-induced epithelium movement and embryonic eyelid closure". The EMBO Journal. 22 (17): 4443–54. doi:10.1093/emboj/cdg440. PMC 202382. PMID 12941696.
  21. Gao M, Labuda T, Xia Y, Gallagher E, Fang D, Liu YC, Karin M (October 2004). "Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase Itch". Science. 306 (5694): 271–5. Bibcode:2004Sci...306..271G. doi:10.1126/science.1099414. PMID 15358865.
  22. Gallagher E, Enzler T, Matsuzawa A, Anzelon-Mills A, Otero D, Holzer R, et al. (January 2007). "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. doi:10.1038/ni1421. PMID 17143273.
  23. Charlaftis N, Suddason T, Wu X, Anwar S, Karin M, Gallagher E (November 2014). "The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines". The EMBO Journal. 33 (21): 2581–96. doi:10.15252/embj.201488351. PMC 4282369. PMID 25260751.
  24. Suddason T, Anwar S, Charlaftis N, Gallagher E (January 2016). "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. doi:10.1016/j.celrep.2015.12.047. PMC 4733086. PMID 26774476.
  25. Kwan R, Burnside J, Kurosaki T, Cheng G (November 2001). "MEKK1 is essential for DT40 cell apoptosis in response to microtubule disruption". Molecular and Cellular Biology. 21 (21): 7183–90. doi:10.1128/MCB.21.21.7183-7190.2001. PMC 99893. PMID 11585901.
  26. Tricker E, Arvand A, Kwan R, Chen GY, Gallagher E, Cheng G (February 2011). "Apoptosis induced by cytoskeletal disruption requires distinct domains of MEKK1". PLOS ONE. 6 (2): e17310. Bibcode:2011PLoSO...617310T. doi:10.1371/journal.pone.0017310. PMC 3045432. PMID 21364884.
  27. "MEKK1 (human)". www.phosphosite.org. Retrieved 2020-02-26.
  28. Matsuzawa A, Tseng PH, Vallabhapurapu S, Luo JL, Zhang W, Wang H, et al. (August 2008). "Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex". Science. 321 (5889): 663–8. Bibcode:2008Sci...321..663M. doi:10.1126/science.1157340. PMC 2669719. PMID 18635759.
  29. Karin M, Gallagher E (March 2009). "TNFR signaling: ubiquitin-conjugated TRAFfic signals control stop-and-go for MAPK signaling complexes". Immunological Reviews. 228 (1): 225–40. doi:10.1111/j.1600-065X.2008.00755.x. PMID 19290931.
  30. "MAP3K1 - My Cancer Genome". www.mycancergenome.org. Retrieved 2020-02-26.
  31. Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, et al. (May 2012). "The landscape of cancer genes and mutational processes in breast cancer". Nature. 486 (7403): 400–4. Bibcode:2012Natur.486..400.. doi:10.1038/nature11017. PMC 3428862. PMID 22722201.
  32. Morrell E, O'Mahony D, Glavan B, Harju-Baker S, Nguyen C, Gunderson S, et al. (January 2018). "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. doi:10.1165/rcmb.2017-0030OC. PMC 5941309. PMID 28858533.
  33. Nelson DS, van Halteren A, Quispel WT, van den Bos C, Bovée JV, Patel B, et al. (June 2015). "MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis". Genes, Chromosomes & Cancer. 54 (6): 361–8. doi:10.1002/gcc.22247. PMID 25899310.
  34. Pearlman A, Loke J, Le Caignec C, White S, Chin L, Friedman A, et al. (December 2010). "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. doi:10.1016/j.ajhg.2010.11.003. PMC 2997363. PMID 21129722.
  35. Goto M, Chow J, Muramoto K, Chiba K, Yamamoto S, Fujita M, et al. (November 2009). "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): 485–95. doi:10.1124/jpet.109.156554. PMID 19684251.
  36. "MAP3K1 mitogen-activated protein kinase kinase kinase 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-05-02.
  37. Zhang Y, Qiu WJ, Chan SC, Han J, He X, Lin SC (May 2002). "Casein kinase I and casein kinase II differentially regulate axin function in Wnt and JNK pathways". The Journal of Biological Chemistry. 277 (20): 17706–12. doi:10.1074/jbc.M111982200. PMID 11884395.
  38. Zhang Y, Neo SY, Han J, Lin SC (August 2000). "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): 25008–14. doi:10.1074/jbc.M002491200. PMID 10829020.
  39. Karandikar M, Xu S, Cobb MH (December 2000). "MEKK1 binds raf-1 and the ERK2 cascade components". The Journal of Biological Chemistry. 275 (51): 40120–7. doi:10.1074/jbc.M005926200. PMID 10969079.
  40. Pomérance M, Multon MC, Parker F, Venot C, Blondeau JP, Tocqué B, Schweighoffer F (September 1998). "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): 24301–4. doi:10.1074/jbc.273.38.24301. PMID 9733714.
  41. Xu S, Cobb MH (December 1997). "MEKK1 binds directly to the c-Jun N-terminal kinases/stress-activated protein kinases". The Journal of Biological Chemistry. 272 (51): 32056–60. doi:10.1074/jbc.272.51.32056. PMID 9405400.
  42. Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M (May 1999). "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): 1297–308. doi:10.1101/gad.13.10.1297. PMC 316725. PMID 10346818.
  43. Saltzman A, Searfoss G, Marcireau C, Stone M, Ressner R, Munro R, et al. (April 1998). "hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity". FEBS Letters. 425 (3): 431–5. doi:10.1016/s0014-5793(98)00287-7. PMID 9563508.
  44. Charlaftis N, Suddason T, Wu X, Anwar S, Karin M, Gallagher E (November 2014). "The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines". The EMBO Journal. 33 (21): 2581–96. doi:10.15252/embj.201488351. PMC 4282369. PMID 25260751.
  45. Gallagher ED, Gutowski S, Sternweis PC, Cobb MH (January 2004). "RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity". The Journal of Biological Chemistry. 279 (3): 1872–7. doi:10.1074/jbc.M309525200. PMID 14581471.
  46. Fanger GR, Johnson NL, Johnson GL (August 1997). "MEK kinases are regulated by EGF and selectively interact with Rac/Cdc42". The EMBO Journal. 16 (16): 4961–72. doi:10.1093/emboj/16.16.4961. PMC 1170131. PMID 9305638.
  47. Christerson LB, Gallagher E, Vanderbilt CA, Whitehurst AW, Wells C, Kazempour R, Sternweis PC, Cobb MH (August 2002). "p115 Rho GTPase activating protein interacts with MEKK1". Journal of Cellular Physiology. 192 (2): 200–8. doi:10.1002/jcp.10125. PMID 12115726.
  48. Xia Y, Wu Z, Su B, Murray B, Karin M (November 1998). "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): 3369–81. doi:10.1101/gad.12.21.3369. PMC 317229. PMID 9808624.
  49. Yujiri T, Nawata R, Takahashi T, Sato Y, Tanizawa Y, Kitamura T, Oka Y (November 2003). "MEK kinase 1 interacts with focal adhesion kinase and regulates insulin receptor substrate-1 expression". The Journal of Biological Chemistry. 278 (6): 3369–81. doi:10.1074/jbc.M206087200. PMID 12458213.

Further reading

  • Lin, A (2006). "The JNK Signaling Pathway (Molecular Biology Intelligence Unit)". Landes Bioscience. 1: 1–97. ISBN 978-1587061202.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.