MAP3K1

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; OMA:MAP3K1 - orthologs
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: 111.88 – 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.

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.

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Election system in the American state of Louisiana Elections in Louisiana Federal government Presidential elections 1812 1816 1820 1824 1828 1832 1836 1840 1844 1848 1852 1856 1860 1864 1868 1872 1876 1880 1884 1888 1892 1896 1900 1904 1908 1912 1916 1920 1924 1928 1932 1936 1940 1944 1948 1952 1956 1960 1964 1968 1972 1976 1980 1984 1988 1992 1996 2000 2004 2008 2012 2016 2020 2024 Presidential primaries Democratic 2000 2004 2008 2012 2016 2020 Republican 2004 2008 2012 2016 2020 U.S. Senate...

Cyprus in the Eurovision Song Contest 2015

Eurovision Song Contest 2015Country CyprusNational selectionSelection processEurovision Song ProjectSelection date(s)Auditions:7 December 201414 December 201421 December 201428 December 20144 January 201511 January 2015Eurochallenges:16 January 201523 January 2015Final:1 February 2015Selected entrantJohn KarayiannisSelected songOne Thing I Should Have DoneSelected songwriter(s)Mike ConnarisGiannis KaragiannisFinals performanceSemi-final resultQualified (6th...

 

新罕布什尔州

坐标：43°11′38″N 71°34′21″W / 43.1938516°N 71.5723953°W / 43.1938516; -71.5723953 此條目需要补充更多来源。 (2017年5月21日)请协助補充多方面可靠来源以改善这篇条目，无法查证的内容可能會因為异议提出而被移除。致使用者：请搜索一下条目的标题（来源搜索：新罕布什尔州 — 网页、新闻、书籍、学术、图像），以检查网络上是否存在该主题的更多可靠来源...

 

豪栄道豪太郎

豪栄道 豪太郎 場所入りする豪栄道基礎情報四股名 澤井 豪太郎→豪栄道 豪太郎本名 澤井 豪太郎愛称 ゴウタロウ、豪ちゃん、GAD[1][2]生年月日 (1986-04-06) 1986年4月6日（38歳）出身 大阪府寝屋川市身長 183cm体重 160kgBMI 47.26所属部屋 境川部屋得意技 右四つ・出し投げ・切り返し・外掛け・首投げ・右下手投げ成績現在の番付 引退最高位 東大関生涯戦歴 696勝493敗...

John H. Cox

American attorney, businessman, broadcaster, and political activist John H. CoxCox in 2017Personal detailsBornJohn Kaplan (1955-07-15) July 15, 1955 (age 68)Chicago, Illinois, U.S.Political partyRepublican (2000–present)Other politicalaffiliationsDemocratic (before 2000)Spouse(s)Nancy (divorced)Sarah CoxChildren4EducationUniversity of Illinois, Chicago(BA)Illinois Institute of Technology(JD)WebsiteCampaign website John Herman Cox (né Kaplan; born July 15, 1955) is an American busines...

 

الله الآب

الله الآبمعلومات عامةجزء من ثالوثالله الجنس ذكر الزَّوج الأم السماوية الابن يسوعالله الابنلوسيفر الدِّين المسيحية سُمِّي باسم إلهأب موجود في عمل الفردوس المفقود يُصوِّر الله تعديل - تعديل مصدري - تعديل ويكي بيانات الله الآب - يعقوب هيرينس. الله الآب هو مصطلح من مصطلحات ال�...

 

Puritans

Subclass of English Reformed Protestants Puritan redirects here. For other uses, see Puritan (disambiguation). Part of a series onPuritansThe Puritan, an 1887 statue by Augustus Saint-Gaudens, in Springfield, Massachusetts BackgroundChristianityProtestantismReformationEnglish ReformationCalvinismAnglicanismArminianismArminianism in the Church of EnglandEnglish DissentersIndependentsNonconformismEnglish PresbyterianismEcclesiastical separatism17th-century denominations in England Crucial theme...

Southern Harmony

Shape note hymn and tune book compiled by William Walker For the composition by William Duckworth, see Southern Harmony (Duckworth). For the Black Crowes album, see The Southern Harmony and Musical Companion. Front cover of The Southern Harmony, and Musical Companion tunebook compiled by William Walker. The Southern Harmony, and Musical Companion is a shape note hymn and tune book compiled by William Walker, first published in 1835. The book is notable for having originated or popularized sev...

 

Name of Mexico

Etymology of the name of Mexico Image of Mexico-Tenochtitlan from the Codex Mendoza Several hypotheses seek to explain the etymology of Mexico which dates, at least, back to 14th century Mesoamerica. Among these are expressions in the Nahuatl language like Place in the middle of the century plant (Mexitli) and Place in the Navel of the Moon (Mēxihco), although there is still no consensus among experts.[1] As far back as 1590, the Theatrum Orbis Terrarum showed that the northern part ...

 

The Tortoise and the Hare (sculpture)

Sculpture in Boston, Massachusetts, U.S. The Tortoise and the HareThe sculpture in 2019ArtistNancy SchönYear1994 (1994)MediumBronze sculptureSubjectThe Tortoise and the HareLocationBoston, Massachusetts, U.S.Coordinates42°20′59.9″N 71°4′34″W / 42.349972°N 71.07611°W / 42.349972; -71.07611 The Tortoise and the Hare is a 1994 bronze sculpture by Nancy Schön, installed in Boston's Copley Square, in the U.S. state of Massachusetts. The work references on...

Ephedra sinica

Species of plant Chinese ephedra(Cao Ma Huang—草麻黄) Ephedra sinica Conservation status Least Concern  (IUCN 3.1)[1] Scientific classification Kingdom: Plantae Clade: Tracheophytes Clade: Gymnospermae Division: Gnetophyta Class: Gnetopsida Order: Ephedrales Family: Ephedraceae Genus: Ephedra Species: E. sinica Binomial name Ephedra sinicaStapf Synonyms[2] Ephedra flava F.P.Sm. Ephedra ma-huang Tang S.Liu Ephedra sinica (also known as Chinese ephedra or Ma&...

 

Bois

Pour les articles homonymes, voir Bois (homonymie). Bûche de chêne. L'ébéniste crée des meubles raffinés en recouvrant leur bois massif de marqueterie composées de bois précieux. (table attribuée à Pierre Gole, XVIIe siècle). Lambris de bois sur façade d'appartements (banlieue d'Amsterdam). Texture de bois-mort. Le bois est un matériau naturel d'origine végétale. Il est constitué par un tissu végétal formant la plus grande partie du tronc des plantes ligneuses. Le bois...

 

ポケモンの一覧 (906-)

ポケットモンスター > ポケットモンスター (架空の生物)/ (ポケットモンスターの登場人物) > ポケモンの一覧 > ポケモンの一覧 (906-) ポケモンの一覧（ポケモンのいちらん）は、ゲームソフト『ポケットモンスターシリーズ』に登場する架空の生物「ポケットモンスター（ポケモン）」の一覧。本項では全1025種のうち、『ポケットモンスター スカーレッ...

Trial garden

An example of an AAS trial of marigolds in the Park Seed Trial Gardens. A trial garden is a type of garden grown specifically for the purpose of testing and evaluating plants. Universities, plant breeders, and garden-industry companies frequently have trial gardens, as do many private and public botanical gardens and professional garden journalists. In the classic trials model, newly developed varieties of plants are compared with the closest similar industry standard plant throughout their l...

 

リバモリウム

モスコビウム ← リバモリウム → テネシン Po↑Lv↓不明 116Lv 周期表 外見 不明 一般特性 名称, 記号, 番号 リバモリウム, Lv, 116 分類 不明 族, 周期, ブロック 16, 7, p 原子量 [293]  電子配置 [Rn] 5f14 6d10 7s2 7p4（推定） 電子殻 2, 8, 18, 32, 32, 18, 6（画像） 物理特性 密度（室温付近） 12.9 (α-Lv) g/cm3 融点 300 (推定) °C 沸点 900 (推定) °C 原子特性 共有結合半径 175 pm そ�...