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P41279

- M3K8_HUMAN

UniProt

P41279 - M3K8_HUMAN

Protein

Mitogen-activated protein kinase kinase kinase 8

Gene

MAP3K8

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 143 (01 Oct 2014)
      Sequence version 2 (19 Jul 2004)
      Previous versions | rss
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    Functioni

    Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.8 Publications

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Cofactori

    Magnesium.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei167 – 1671ATPPROSITE-ProRule annotation
    Active sitei253 – 2531Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi144 – 1529ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. magnesium ion binding Source: InterPro
    3. MAP kinase kinase kinase activity Source: UniProtKB-EC
    4. protein binding Source: IntAct
    5. protein serine/threonine kinase activity Source: ProtInc

    GO - Biological processi

    1. cell cycle Source: UniProtKB-KW
    2. protein phosphorylation Source: ProtInc
    3. T cell costimulation Source: Reactome

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Cell cycle, Immunity

    Keywords - Ligandi

    ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

    Enzyme and pathway databases

    ReactomeiREACT_19358. CD28 dependent PI3K/Akt signaling.
    REACT_22442. Interleukin-1 signaling.
    SignaLinkiP41279.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Mitogen-activated protein kinase kinase kinase 8 (EC:2.7.11.25)
    Alternative name(s):
    Cancer Osaka thyroid oncogene
    Proto-oncogene c-Cot
    Serine/threonine-protein kinase cot
    Tumor progression locus 2
    Short name:
    TPL-2
    Gene namesi
    Name:MAP3K8
    Synonyms:COT, ESTF
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 10

    Organism-specific databases

    HGNCiHGNC:6860. MAP3K8.

    Subcellular locationi

    Cytoplasm 2 Publications

    GO - Cellular componenti

    1. cytoplasm Source: HPA
    2. cytosol Source: Reactome

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi62 – 621S → A: Decreased IL1-stimulated activity. Loss of IL1-stimulated phosphorylation of T-290 and MEK phosphorylation activity; when associated with A-400. 1 Publication
    Mutagenesisi167 – 1671K → R: Loss of catalytic activity. 1 Publication
    Mutagenesisi270 – 2701D → A: Loss of catalytic activity. 1 Publication
    Mutagenesisi290 – 2901T → A: Loss of MEK phosphorylation activity and almost abolished autophosphorylation activity. Loss of IL1-stimulated MEK phosphorylation activity but not of IL1-stimulated autophosphorylation activity. No effect on KSR2 binding. 2 Publications
    Mutagenesisi290 – 2901T → D: Impaired MEK phosphorylation and autophosphorylation activities. No effect on KSR2 binding. 2 Publications
    Mutagenesisi290 – 2901T → E: Loss of MEK phosphorylation activity and almost abolished autophosphorylation activity. No effect on KSR2 binding. 2 Publications
    Mutagenesisi400 – 4001S → A: Slightly decreased IL1-stimulated MEK phosphorylation activity. Loss of IL1-stimulated phosphorylation of T-290 and MEK phosphorylation activity; when associated with A-62. 1 Publication

    Keywords - Diseasei

    Proto-oncogene

    Organism-specific databases

    PharmGKBiPA30606.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 467467Mitogen-activated protein kinase kinase kinase 8PRO_0000024350Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei62 – 621Phosphoserine; by autocatalysis1 Publication
    Modified residuei80 – 801Phosphothreonine1 Publication
    Modified residuei290 – 2901Phosphothreonine3 Publications
    Modified residuei400 – 4001Phosphoserine3 Publications
    Modified residuei443 – 4431Phosphoserine1 Publication

    Post-translational modificationi

    Autophosphorylated. Isoform 1 undergoes phosphorylation mainly on Ser residues, and isoform 2 on both Ser and Thr residues. Thr-290 is autophosphorylated (PubMed:19754427) and/or transphosphorylated (PubMed:15466476); the phosphorylation is necessary but not sufficient for full kinase activity in vitro and for the dissociation of isoform 1 from NFKB1, leading to its degradation. Ser-400 is autophosphorylated (PubMed:19754427) and/or transphosphorylated by IKBKB (PubMed:22988300); the phosphorylation is required for LPS-stimulated activation of the MAPK/ERK pathway in macrophages.5 Publications

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    PaxDbiP41279.
    PRIDEiP41279.

    PTM databases

    PhosphoSiteiP41279.

    Expressioni

    Tissue specificityi

    Expressed in several normal tissues and human tumor-derived cell lines.

    Developmental stagei

    Isoform 1 is activated specifically during the S and G2/M phases of the cell cycle.

    Inductioni

    Up-regulated by IL12 in T-lymphocytes. Up-regulated in subcutaneous adipose tissue of obese individuals.2 Publications

    Gene expression databases

    ArrayExpressiP41279.
    BgeeiP41279.
    CleanExiHS_MAP3K8.
    GenevestigatoriP41279.

    Organism-specific databases

    HPAiCAB005120.
    HPA017962.

    Interactioni

    Subunit structurei

    Forms a ternary complex with NFKB1/p105 and TNIP2. Interacts with NFKB1; the interaction increases the stability of MAP3K8 but inhibits its MEK phosphorylation activity, whereas loss of interaction following LPS stimulation leads to its degradation. Interacts with CD40 and TRAF6; the interaction is required for ERK activation. Interacts with KSR2; the interaction inhibits ERK and NF-kappa-B activation.5 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    HSP90AB1P082382EBI-354900,EBI-352572
    NFKB1P198382EBI-354900,EBI-300010
    TNIP2Q8NFZ59EBI-354900,EBI-359372

    Protein-protein interaction databases

    BioGridi107719. 20 interactions.
    DIPiDIP-27534N.
    IntActiP41279. 11 interactions.
    MINTiMINT-1140505.
    STRINGi9606.ENSP00000263056.

    Structurei

    3D structure databases

    ProteinModelPortaliP41279.
    SMRiP41279. Positions 88-438.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini138 – 388251Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    HOGENOMiHOG000285978.
    HOVERGENiHBG006306.
    InParanoidiP41279.
    KOiK04415.
    OMAiIHLFMEA.
    OrthoDBiEOG71P29J.
    PhylomeDBiP41279.
    TreeFamiTF105117.

    Family and domain databases

    InterProiIPR011009. Kinase-like_dom.
    IPR017424. MAPKKK8.
    IPR000719. Prot_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    PIRSFiPIRSF038171. MAPKKK8. 1 hit.
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative initiation. Align

    Isoform 1 (identifier: P41279-1) [UniParc]FASTAAdd to Basket

    Also known as: 58 kDa

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MEYMSTGSDN KEEIDLLIKH LNVSDVIDIM ENLYASEEPA VYEPSLMTMC    50
    QDSNQNDERS KSLLLSGQEV PWLSSVRYGT VEDLLAFANH ISNTAKHFYG 100
    QRPQESGILL NMVITPQNGR YQIDSDVLLI PWKLTYRNIG SDFIPRGAFG 150
    KVYLAQDIKT KKRMACKLIP VDQFKPSDVE IQACFRHENI AELYGAVLWG 200
    ETVHLFMEAG EGGSVLEKLE SCGPMREFEI IWVTKHVLKG LDFLHSKKVI 250
    HHDIKPSNIV FMSTKAVLVD FGLSVQMTED VYFPKDLRGT EIYMSPEVIL 300
    CRGHSTKADI YSLGATLIHM QTGTPPWVKR YPRSAYPSYL YIIHKQAPPL 350
    EDIADDCSPG MRELIEASLE RNPNHRPRAA DLLKHEALNP PREDQPRCQS 400
    LDSALLERKR LLSRKELELP ENIADSSCTG STEESEMLKR QRSLYIDLGA 450
    LAGYFNLVRG PPTLEYG 467
    Length:467
    Mass (Da):52,925
    Last modified:July 19, 2004 - v2
    Checksum:i7728969EA3E4E8EC
    GO
    Isoform 2 (identifier: P41279-2) [UniParc]FASTAAdd to Basket

    Also known as: 52 kDa

    The sequence of this isoform differs from the canonical sequence as follows:
         1-29: Missing.

    Show »
    Length:438
    Mass (Da):49,620
    Checksum:i2121FEF4658882FD
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti399 – 3991Q → T in BAA03387. (PubMed:2072910)Curated
    Sequence conflicti399 – 3991Q → T no nucleotide entry (PubMed:8226782)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti214 – 2141S → F.
    Corresponds to variant rs3087944 [ dbSNP | Ensembl ].
    VAR_051638
    Natural varianti398 – 41518CQSLD…LLSRK → GHQVIHEGSSTNDPNNSC in oncogenic form.
    VAR_006198Add
    BLAST
    Natural varianti416 – 46752Missing in oncogenic form.
    VAR_006199Add
    BLAST

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 2929Missing in isoform 2. 1 PublicationVSP_018843Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D14497 mRNA. Translation: BAA03387.1.
    Z14138 mRNA. Translation: CAA78512.1.
    AK290320 mRNA. Translation: BAF83009.1.
    AY309013 Genomic DNA. Translation: AAP45053.1.
    AL161651 Genomic DNA. Translation: CAI14227.1.
    CH471072 Genomic DNA. Translation: EAW86004.1.
    CH471072 Genomic DNA. Translation: EAW86005.1.
    CH471072 Genomic DNA. Translation: EAW86006.1.
    CH471072 Genomic DNA. Translation: EAW86007.1.
    BC104833 mRNA. Translation: AAI04834.1.
    BC113566 mRNA. Translation: AAI13567.1.
    AF133211 Genomic DNA. Translation: AAG13454.1.
    CCDSiCCDS7166.1. [P41279-1]
    PIRiA48713.
    RefSeqiNP_001231063.1. NM_001244134.1. [P41279-1]
    NP_005195.2. NM_005204.3. [P41279-1]
    XP_005252421.2. XM_005252364.2. [P41279-1]
    XP_005252423.1. XM_005252366.1. [P41279-1]
    UniGeneiHs.432453.
    Hs.731448.

    Genome annotation databases

    EnsembliENST00000263056; ENSP00000263056; ENSG00000107968. [P41279-1]
    ENST00000375321; ENSP00000364470; ENSG00000107968. [P41279-1]
    ENST00000542547; ENSP00000443610; ENSG00000107968. [P41279-1]
    GeneIDi1326.
    KEGGihsa:1326.
    UCSCiuc001ivi.2. human. [P41279-1]

    Polymorphism databases

    DMDMi50403742.

    Keywords - Coding sequence diversityi

    Alternative initiation, Polymorphism

    Cross-referencesi

    Web resourcesi

    SeattleSNPs

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    D14497 mRNA. Translation: BAA03387.1 .
    Z14138 mRNA. Translation: CAA78512.1 .
    AK290320 mRNA. Translation: BAF83009.1 .
    AY309013 Genomic DNA. Translation: AAP45053.1 .
    AL161651 Genomic DNA. Translation: CAI14227.1 .
    CH471072 Genomic DNA. Translation: EAW86004.1 .
    CH471072 Genomic DNA. Translation: EAW86005.1 .
    CH471072 Genomic DNA. Translation: EAW86006.1 .
    CH471072 Genomic DNA. Translation: EAW86007.1 .
    BC104833 mRNA. Translation: AAI04834.1 .
    BC113566 mRNA. Translation: AAI13567.1 .
    AF133211 Genomic DNA. Translation: AAG13454.1 .
    CCDSi CCDS7166.1. [P41279-1 ]
    PIRi A48713.
    RefSeqi NP_001231063.1. NM_001244134.1. [P41279-1 ]
    NP_005195.2. NM_005204.3. [P41279-1 ]
    XP_005252421.2. XM_005252364.2. [P41279-1 ]
    XP_005252423.1. XM_005252366.1. [P41279-1 ]
    UniGenei Hs.432453.
    Hs.731448.

    3D structure databases

    ProteinModelPortali P41279.
    SMRi P41279. Positions 88-438.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 107719. 20 interactions.
    DIPi DIP-27534N.
    IntActi P41279. 11 interactions.
    MINTi MINT-1140505.
    STRINGi 9606.ENSP00000263056.

    Chemistry

    BindingDBi P41279.
    ChEMBLi CHEMBL4899.
    GuidetoPHARMACOLOGYi 2083.

    PTM databases

    PhosphoSitei P41279.

    Polymorphism databases

    DMDMi 50403742.

    Proteomic databases

    PaxDbi P41279.
    PRIDEi P41279.

    Protocols and materials databases

    DNASUi 1326.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000263056 ; ENSP00000263056 ; ENSG00000107968 . [P41279-1 ]
    ENST00000375321 ; ENSP00000364470 ; ENSG00000107968 . [P41279-1 ]
    ENST00000542547 ; ENSP00000443610 ; ENSG00000107968 . [P41279-1 ]
    GeneIDi 1326.
    KEGGi hsa:1326.
    UCSCi uc001ivi.2. human. [P41279-1 ]

    Organism-specific databases

    CTDi 1326.
    GeneCardsi GC10P030722.
    HGNCi HGNC:6860. MAP3K8.
    HPAi CAB005120.
    HPA017962.
    MIMi 191195. gene.
    neXtProti NX_P41279.
    PharmGKBi PA30606.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0515.
    HOGENOMi HOG000285978.
    HOVERGENi HBG006306.
    InParanoidi P41279.
    KOi K04415.
    OMAi IHLFMEA.
    OrthoDBi EOG71P29J.
    PhylomeDBi P41279.
    TreeFami TF105117.

    Enzyme and pathway databases

    Reactomei REACT_19358. CD28 dependent PI3K/Akt signaling.
    REACT_22442. Interleukin-1 signaling.
    SignaLinki P41279.

    Miscellaneous databases

    GeneWikii MAP3K8.
    GenomeRNAii 1326.
    NextBioi 5403.
    PROi P41279.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P41279.
    Bgeei P41279.
    CleanExi HS_MAP3K8.
    Genevestigatori P41279.

    Family and domain databases

    InterProi IPR011009. Kinase-like_dom.
    IPR017424. MAPKKK8.
    IPR000719. Prot_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view ]
    Pfami PF00069. Pkinase. 1 hit.
    [Graphical view ]
    PIRSFi PIRSF038171. MAPKKK8. 1 hit.
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Structure and transforming potential of the human cot oncogene encoding a putative protein kinase."
      Miyoshi J., Higashi T., Mukai H., Ohuchi T., Kakunaga T.
      Mol. Cell. Biol. 11:4088-4096(1991) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), ONCOGENIC VARIANT.
      Tissue: Hepatoma.
    2. "The human cot proto-oncogene encodes two protein serine/threonine kinases with different transforming activities by alternative initiation of translation."
      Aoki M., Sugimoto T., Sumida S., Hamada F., Akiyama T., Toyoshima K.
      J. Biol. Chem. 268:22723-22732(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), SUBCELLULAR LOCATION.
    3. "Expression cDNA cloning of a serine kinase transforming gene."
      Chan A.M., Chedid M., McGovern E.S., Popescu N.C., Miki T., Aaronson S.A.
      Oncogene 8:1329-1333(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
      Tissue: Bone.
    4. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
      Tissue: Tongue.
    5. SeattleSNPs variation discovery resource
      Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    6. "The DNA sequence and comparative analysis of human chromosome 10."
      Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J.
      , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.
      Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    7. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    8. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
      Tissue: Brain.
    9. "COT kinase proto-oncogene expression in T cells: implication of the JNK/SAPK signal transduction pathway in COT promoter activation."
      Sanchez-Gongora E., Lisbona C., de Gregorio R., Ballester A., Calvo V., Perez-Jurado L., Alemany S.
      J. Biol. Chem. 275:31379-31386(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-112.
      Tissue: T-cell.
    10. "Identification and characterization of protein products of the cot oncogene with serine kinase activity."
      Aoki M., Akiyama T., Miyoshi J., Toyoshima K.
      Oncogene 6:1515-1519(1991) [PubMed] [Europe PMC] [Abstract]
      Cited for: ALTERNATIVE INITIATION, FUNCTION, SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION.
    11. "TPL-2 kinase regulates the proteolysis of the NF-kappaB-inhibitory protein NF-kappaB1 p105."
      Belich M.P., Salmeron A., Johnston L.H., Ley S.C.
      Nature 397:363-368(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH NFKB1.
    12. "p27kip protein levels and E2F activity are targets of Cot kinase during G1 phase progression in T cells."
      Velasco-Sampayo A., Alemany S.
      J. Immunol. 166:6084-6090(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    13. "Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling."
      Channavajhala P.L., Wu L., Cuozzo J.W., Hall J.P., Liu W., Lin L.-L., Zhang Y.
      J. Biol. Chem. 278:47089-47097(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH KSR2.
    14. "NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase."
      Waterfield M.R., Zhang M., Norman L.P., Sun S.C.
      Mol. Cell 11:685-694(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH NFKB1.
    15. "Phosphorylation of threonine 290 in the activation loop of Tpl2/Cot is necessary but not sufficient for kinase activity."
      Luciano B.S., Hsu S., Channavajhala P.L., Lin L.L., Cuozzo J.W.
      J. Biol. Chem. 279:52117-52123(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-290, INTERACTION WITH KSR2, MUTAGENESIS OF THR-290.
    16. "ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability."
      Lang V., Symons A., Watton S.J., Janzen J., Soneji Y., Beinke S., Howell S., Ley S.C.
      Mol. Cell. Biol. 24:5235-5248(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH NFKB1 AND TNIP2.
    17. "Phosphorylation at Thr-290 regulates Tpl2 binding to NF-kappaB1/p105 and Tpl2 activation and degradation by lipopolysaccharide."
      Cho J., Tsichlis P.N.
      Proc. Natl. Acad. Sci. U.S.A. 102:2350-2355(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-290.
    18. "TRAF6 and Src kinase activity regulates Cot activation by IL-1."
      Rodriguez C., Pozo M., Nieto E., Fernandez M., Alemany S.
      Cell. Signal. 18:1376-1385(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    19. "Characterization of phosphorylation sites on Tpl2 using IMAC enrichment and a linear ion trap mass spectrometer."
      Black T.M., Andrews C.L., Kilili G., Ivan M., Tsichlis P.N., Vouros P.
      J. Proteome Res. 6:2269-2276(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT THR-80; SER-400 AND SER-443.
    20. Cited for: FUNCTION, INDUCTION.
    21. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    22. "IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2."
      Handoyo H., Stafford M.J., McManus E., Baltzis D., Peggie M., Cohen P.
      Biochem. J. 424:109-118(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, PHOSPHORYLATION AT SER-62; THR-290 AND SER-400, MUTAGENESIS OF SER-62; LYS-167; ASP-270; THR-290 AND SER-400.
    23. "Tpl2 kinase is upregulated in adipose tissue in obesity and may mediate interleukin-1beta and tumor necrosis factor-{alpha} effects on extracellular signal-regulated kinase activation and lipolysis."
      Jager J., Gremeaux T., Gonzalez T., Bonnafous S., Debard C., Laville M., Vidal H., Tran A., Gual P., Le Marchand-Brustel Y., Cormont M., Tanti J.F.
      Diabetes 59:61-70(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INDUCTION.
    24. "IkappaB kinase 2 regulates TPL-2 activation of extracellular signal-regulated kinases 1 and 2 by direct phosphorylation of TPL-2 serine 400."
      Roget K., Ben-Addi A., Mambole-Dema A., Gantke T., Yang H.T., Janzen J., Morrice N., Abbott D., Ley S.C.
      Mol. Cell. Biol. 32:4684-4690(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-400.

    Entry informationi

    Entry nameiM3K8_HUMAN
    AccessioniPrimary (citable) accession number: P41279
    Secondary accession number(s): A8K2Q5
    , D3DRX1, Q14275, Q5T855, Q9HC81
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 1, 1995
    Last sequence update: July 19, 2004
    Last modified: October 1, 2014
    This is version 143 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Miscellaneous

    Can be converted to an oncogenic protein by proviral activation, leading to a C-terminally truncated protein with transforming activity.

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 10
      Human chromosome 10: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3