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D3ZSZ3

- NLK_RAT

UniProt

D3ZSZ3 - NLK_RAT

Protein

Serine/threonine-protein kinase NLK

Gene

Nlk

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Protein inferred from homologyi
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    • History
      Entry version 37 (01 Oct 2014)
      Sequence version 1 (20 Apr 2010)
      Previous versions | rss
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    Functioni

    Serine/threonine-protein kinase that regulates a number of transcription factors with key roles in cell fate determination. Positive effector of the non-canonical Wnt signaling pathway, acting downstream of WNT5A, MAP3K7/TAK1 and HIPK2. Activation of this pathway causes binding to and phosphorylation of the histone methyltransferase SETDB1. The NLK-SETDB1 complex subsequently interacts with PPARG, leading to methylation of PPARG target promoters at histone H3K9 and transcriptional silencing. The resulting loss of PPARG target gene transcription inhibits adipogenesis and promotes osteoblastogenesis in mesenchymal stem cells (MSCs). Negative regulator of the canonical Wnt/beta-catenin signaling pathway. Binds to and phosphorylates TCF7L2/TCF4 and LEF1, promoting the dissociation of the TCF7L2/LEF1/beta-catenin complex from DNA, as well as the ubiquitination and subsequent proteolysis of LEF1. Together these effects inhibit the transcriptional activation of canonical Wnt/beta-catenin target genes. Negative regulator of the Notch signaling pathway. Binds to and phosphorylates NOTCH1, thereby preventing the formation of a transcriptionally active ternary complex of NOTCH1, RBPJ/RBPSUH and MAML1. Negative regulator of the MYB family of transcription factors. Phosphorylation of MYB leads to its subsequent proteolysis while phosphorylation of MYBL1 and MYBL2 inhibits their interaction with the coactivator CREBBP. Other transcription factors may also be inhibited by direct phosphorylation of CREBBP itself. Acts downstream of IL6 and MAP3K7/TAK1 to phosphorylate STAT3, which is in turn required for activation of NLK by MAP3K7/TAK1 By similarity.By similarity

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Cofactori

    Magnesium.By similarity

    Enzyme regulationi

    Activated by the non-canonical Wnt signaling pathway, in which WNT5A leads to activation of MAP3K7/TAK1 and HIPK2, which subsequently phosphorylates and activates this protein. Activated by dimerization and subsequent intermolecular autophosphorylation on Thr-298. Other cytokines such as IL6 may also activate this regulatory circuit By similarity.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei167 – 1671ATPPROSITE-ProRule annotation
    Active sitei264 – 2641Proton 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: Ensembl
    3. MAP kinase activity Source: UniProtKB-EC

    GO - Biological processi

    1. negative regulation of Wnt signaling pathway Source: Ensembl
    2. peptidyl-threonine phosphorylation Source: Ensembl
    3. protein autophosphorylation Source: Ensembl
    4. regulation of transcription, DNA-templated Source: UniProtKB-KW
    5. serine phosphorylation of STAT3 protein Source: Ensembl
    6. transcription, DNA-templated Source: UniProtKB-KW
    7. transforming growth factor beta receptor signaling pathway Source: Ensembl
    8. Wnt signaling pathway Source: UniProtKB-KW

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Transcription, Transcription regulation, Wnt signaling pathway

    Keywords - Ligandi

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

    Enzyme and pathway databases

    ReactomeiREACT_194690. Ca2+ pathway.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Serine/threonine-protein kinase NLK (EC:2.7.11.24)
    Alternative name(s):
    Nemo-like kinase
    Gene namesi
    Name:Nlk
    OrganismiRattus norvegicus (Rat)
    Taxonomic identifieri10116 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
    ProteomesiUP000002494: Chromosome 10

    Organism-specific databases

    RGDi1561602. Nlk.

    Subcellular locationi

    Nucleus By similarity. Cytoplasm By similarity
    Note: Predominantly nuclear. A smaller fraction is cytoplasmic By similarity.By similarity

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB-SubCell
    2. nucleus Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 527527Serine/threonine-protein kinase NLKPRO_0000413531Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei298 – 2981PhosphothreonineBy similarity
    Modified residuei522 – 5221PhosphoserineBy similarity

    Post-translational modificationi

    Phosphorylated on Thr-298. Intermolecular autophosphorylation on Thr-298 activates the enzyme By similarity.By similarity

    Keywords - PTMi

    Phosphoprotein

    Interactioni

    Subunit structurei

    Homodimer. Homodimerization is required for intermolecular autophosphorylation, kinase activation and nuclear localization. Interacts with the upstream activating kinases HIPK2 and MAP3K7/TAK1. Interaction with MAP3K7/TAK1 seems to be indirect, and may be mediated by other proteins such as STAT3, TAB1 and TAB2. Interacts with and phosphorylates a number of transcription factors including FOXO1, FOXO3, FOXO4, LEF1, MYB, MYBL1, MYBL2, NOTCH1 and TCF7L2/TCF4. Interacts with DAPK3/ZIPK, and this interaction may disrupt interaction with transcription factors such as TCF7L2/TCF. Forms a complex with CHD7, PPARG and SETDB1 in response to WNT5A signaling. May interact with components of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes. Interacts with RNF138/NARF. Interacts with MEF2A By similarity.By similarity

    Structurei

    3D structure databases

    ProteinModelPortaliD3ZSZ3.
    SMRiD3ZSZ3. Positions 144-521.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini138 – 427290Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni1 – 304304Required for interaction with TAB2By similarityAdd
    BLAST
    Regioni1 – 125125Sufficient for interaction with DAPK3By similarityAdd
    BLAST
    Regioni124 – 416293Sufficient for interaction with DAPK3By similarityAdd
    BLAST
    Regioni428 – 527100Required for homodimerization and kinase activation and localization to the nucleusBy similarityAdd
    BLAST
    Regioni434 – 52794Required for interaction with TAB2By similarityAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi298 – 3003TQE

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi22 – 254Poly-Ala
    Compositional biasi27 – 6741His-richAdd
    BLAST
    Compositional biasi27 – 348Poly-His
    Compositional biasi42 – 487Poly-His
    Compositional biasi58 – 12366Ala-richAdd
    BLAST
    Compositional biasi71 – 8313Poly-AlaAdd
    BLAST
    Compositional biasi106 – 1116Poly-Ala
    Compositional biasi115 – 1195Poly-Ala

    Domaini

    Contains a TQE activation loop motif in which autophosphorylation of the threonine residue (Thr-298) is sufficient for kinase activation. This mode of activation contrasts with that of classical MAP kinases, which contain a TXY activation loop motif in which phosphorylation of both the threonine and tyrosine residues is required for kinase activation (By similarity).By similarity

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    GeneTreeiENSGT00730000110881.
    KOiK04468.
    OMAiCKCCYTT.
    OrthoDBiEOG72RMZ3.
    PhylomeDBiD3ZSZ3.
    TreeFamiTF315210.

    Family and domain databases

    InterProiIPR011009. Kinase-like_dom.
    IPR003527. MAP_kinase_CS.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    SMARTiSM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS01351. MAPK. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    D3ZSZ3-1 [UniParc]FASTAAdd to Basket

    « Hide

    MSLCGTRANA KMMAAYNGGT SAAAAGHHHH HHHHLPHLPP PHLHHHHHPQ    50
    HHLHPGSAAA VHPVQQHTSS AAAAAAAAAA AAAMLNPGQQ QPYFPSPAPG 100
    QAPGPAAAAP AQVQAAAAAT VKAHHHQHSH HPQQQLDIEP DRPIGYGAFG 150
    VVWSVTDPRD GKRVALKKMP NVFQNLVSCK RVFRELKMLC FFKHDNVLSA 200
    LDILQPPHID YFEEIYVVTE LMQSDLHKII VSPQPLSSDH VKVFLYQILR 250
    GLKYLHSAGI LHRDIKPGNL LVNSNCVLKI CDFGLARVEE LDESRHMTQE 300
    VVTQYYRAPE ILMGSRHYSN AIDIWSVGCI FAELLGRRIL FQAQSPIQQL 350
    DLITDLLGTP SLEAMRTACE GAKAHILRGP HKQPSLPVLY TLSSQATHEA 400
    VHLLCRMLVF DPSKRISAKD ALAHPYLDEG RLRYHTCMCK CCFSTSTGRV 450
    YTSDFEPVTN PKFDDTFEKN LSSVRQVKEI IHQFILEQQK GNRVPLCINP 500
    QSAAFKSFIS STVAQPSEMP PSPLVWE 527
    Length:527
    Mass (Da):58,313
    Last modified:April 20, 2010 - v1
    Checksum:iCE6D5DCCB9133989
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AABR03073152 Genomic DNA. No translation available.
    RefSeqiNP_001178853.1. NM_001191924.1.
    XP_006247007.1. XM_006246945.1.
    XP_006247008.1. XM_006246946.1.
    UniGeneiRn.113514.

    Genome annotation databases

    EnsembliENSRNOT00000011726; ENSRNOP00000011726; ENSRNOG00000008704.
    GeneIDi497961.
    KEGGirno:497961.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AABR03073152 Genomic DNA. No translation available.
    RefSeqi NP_001178853.1. NM_001191924.1.
    XP_006247007.1. XM_006246945.1.
    XP_006247008.1. XM_006246946.1.
    UniGenei Rn.113514.

    3D structure databases

    ProteinModelPortali D3ZSZ3.
    SMRi D3ZSZ3. Positions 144-521.
    ModBasei Search...
    MobiDBi Search...

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSRNOT00000011726 ; ENSRNOP00000011726 ; ENSRNOG00000008704 .
    GeneIDi 497961.
    KEGGi rno:497961.

    Organism-specific databases

    CTDi 51701.
    RGDi 1561602. Nlk.

    Phylogenomic databases

    GeneTreei ENSGT00730000110881.
    KOi K04468.
    OMAi CKCCYTT.
    OrthoDBi EOG72RMZ3.
    PhylomeDBi D3ZSZ3.
    TreeFami TF315210.

    Enzyme and pathway databases

    Reactomei REACT_194690. Ca2+ pathway.

    Miscellaneous databases

    NextBioi 698209.
    PROi D3ZSZ3.

    Family and domain databases

    InterProi IPR011009. Kinase-like_dom.
    IPR003527. MAP_kinase_CS.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view ]
    Pfami PF00069. Pkinase. 1 hit.
    [Graphical view ]
    SMARTi SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS01351. MAPK. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Genome sequence of the Brown Norway rat yields insights into mammalian evolution."
      Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J., Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G., Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G., Morgan M.
      , Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G., Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S., Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T., Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D., Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L., Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D., Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M., Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C., Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J., Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H., Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X., Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q., Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P., Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A., Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C., Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J., Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J., Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F., Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A., Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A., Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J., Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E., Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M., Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C., Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L., Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W., Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y., Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V., Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M., Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S., Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B., Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R., Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J., Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D., Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S., Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S., Mockrin S., Collins F.S.
      Nature 428:493-521(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
      Strain: Brown Norway.

    Entry informationi

    Entry nameiNLK_RAT
    AccessioniPrimary (citable) accession number: D3ZSZ3
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 19, 2011
    Last sequence update: April 20, 2010
    Last modified: October 1, 2014
    This is version 37 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3