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Q9JI10

- STK3_MOUSE

UniProt

Q9JI10 - STK3_MOUSE

Protein

Serine/threonine-protein kinase 3

Gene

Stk3

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 120 (01 Oct 2014)
      Sequence version 1 (01 Oct 2000)
      Previous versions | rss
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    Functioni

    Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation. Phosphorylates NKX2-1. Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosomes, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38 By similarity.By similarity

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Cofactori

    Magnesium.By similarity

    Enzyme regulationi

    Inhibited by the C-terminal non-catalytic region. Activated by caspase-cleavage. Full activation also requires homodimerization and autophosphorylation of Thr-180, which are inhibited by the proto-oncogene product RAF1. Activated by RASSF1 which acts by preventing its dephosphorylation By similarity.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei56 – 561ATPPROSITE-ProRule annotation
    Active sitei146 – 1461Proton acceptorPROSITE-ProRule annotation
    Sitei322 – 3232Cleavage; by caspase-3

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi33 – 419ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB
    2. magnesium ion binding Source: UniProtKB
    3. protein dimerization activity Source: UniProtKB
    4. protein serine/threonine kinase activity Source: UniProtKB

    GO - Biological processi

    1. cell differentiation involved in embryonic placenta development Source: MGI
    2. central nervous system development Source: MGI
    3. endocardium development Source: MGI
    4. hepatocyte apoptotic process Source: MGI
    5. hippo signaling Source: UniProtKB
    6. intracellular signal transduction Source: UniProtKB
    7. negative regulation of canonical Wnt signaling pathway Source: MGI
    8. negative regulation of cell proliferation Source: MGI
    9. negative regulation of organ growth Source: MGI
    10. neural tube formation Source: MGI
    11. positive regulation of apoptotic process Source: UniProtKB
    12. positive regulation of extrinsic apoptotic signaling pathway via death domain receptors Source: MGI
    13. positive regulation of JNK cascade Source: MGI
    14. positive regulation of protein kinase B signaling Source: MGI
    15. primitive hemopoiesis Source: MGI
    16. protein phosphorylation Source: UniProtKB

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Apoptosis

    Keywords - Ligandi

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

    Enzyme and pathway databases

    ReactomeiREACT_196537. Signaling by Hippo.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Serine/threonine-protein kinase 3 (EC:2.7.11.1)
    Alternative name(s):
    Mammalian STE20-like protein kinase 2
    Short name:
    MST-2
    STE20-like kinase MST2
    Cleaved into the following 2 chains:
    Gene namesi
    Name:Stk3
    Synonyms:Mess1, Mst2
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 15

    Organism-specific databases

    MGIiMGI:1928487. Stk3.

    Subcellular locationi

    Cytoplasm By similarity. Nucleus By similarity
    Note: The caspase-cleaved form cycles between nucleus and cytoplasm. Phosphorylation at Thr-117 leads to inhibition of nuclear translocation By similarity.By similarity

    GO - Cellular componenti

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

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Disruption phenotypei

    Mice show progressive hepatomegaly with a 2-fold increase in liver mass relative to total body mass at 1 month of age and a 3-fold increase by 3 months of age.1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 497497Serine/threonine-protein kinase 3PRO_0000086690Add
    BLAST
    Chaini1 – 322322Serine/threonine-protein kinase 3 36kDa subunitPRO_0000413715Add
    BLAST
    Chaini323 – 497175Serine/threonine-protein kinase 3 20kDa subunitPRO_0000413716Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei1 – 11N-acetylmethionineBy similarity
    Modified residuei15 – 151PhosphoserineBy similarity
    Modified residuei117 – 1171Phosphothreonine; by PKB/AKT1By similarity
    Modified residuei180 – 1801Phosphothreonine; by autocatalysisBy similarity
    Modified residuei316 – 3161Phosphoserine2 Publications
    Modified residuei336 – 3361PhosphothreonineBy similarity
    Modified residuei390 – 3901Phosphothreonine; by PKB/AKT1By similarity
    Modified residuei450 – 4501PhosphoserineBy similarity

    Post-translational modificationi

    Phosphorylation at Thr-117 and Thr-390 by PKB/AKT1, leads to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation, and increase in its binding to RAF1.By similarity
    Proteolytically cleaved by caspase-3 during apoptosis. Proteolytic cleavage results in kinase activation and nuclear translocation of the truncated form (MST1/N).1 Publication

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiQ9JI10.
    PaxDbiQ9JI10.
    PRIDEiQ9JI10.

    PTM databases

    PhosphoSiteiQ9JI10.

    Expressioni

    Gene expression databases

    ArrayExpressiQ9JI10.
    BgeeiQ9JI10.
    CleanExiMM_STK3.
    GenevestigatoriQ9JI10.

    Interactioni

    Subunit structurei

    Homodimer; mediated via the coiled-coil region. Interacts with NORE1, which inhibits autoactivation. Interacts with and stabilizes SAV1. Interacts with RAF1, which prevents dimerization and phosphorylation. Interacts with RASSF1. Interacts (via SARAH domain) with NEK2 By similarity. Interacts with ESR1 only in the presence of SAV1. Interacts with PKB/AKT1. Forms a tripartite complex with MOBKL1B and STK38. Interacts with RASSF2 (via SARAH domain) By similarity.By similarity

    Protein-protein interaction databases

    BioGridi207869. 1 interaction.
    IntActiQ9JI10. 1 interaction.

    Structurei

    3D structure databases

    ProteinModelPortaliQ9JI10.
    SMRiQ9JI10. Positions 10-494.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini27 – 278252Protein kinasePROSITE-ProRule annotationAdd
    BLAST
    Domaini443 – 49048SARAHPROSITE-ProRule annotationAdd
    BLAST

    Coiled coil

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Coiled coili287 – 32842Sequence AnalysisAdd
    BLAST
    Coiled coili366 – 38722Sequence AnalysisAdd
    BLAST
    Coiled coili448 – 47932Sequence AnalysisAdd
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi293 – 38189Glu-richAdd
    BLAST
    Compositional biasi308 – 3147Poly-Glu
    Compositional biasi370 – 38112Poly-GluAdd
    BLAST

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation
    Contains 1 SARAH domain.PROSITE-ProRule annotation

    Keywords - Domaini

    Coiled coil

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00640000091192.
    HOGENOMiHOG000234203.
    HOVERGENiHBG108518.
    InParanoidiQ9JI10.
    KOiK04412.
    OMAiXDEDELD.
    OrthoDBiEOG7TF79T.
    PhylomeDBiQ9JI10.
    TreeFamiTF354217.

    Family and domain databases

    InterProiIPR011009. Kinase-like_dom.
    IPR024205. Mst1_SARAH_domain.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR011524. SARAH_dom.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    [Graphical view]
    PfamiPF11629. Mst1_SARAH. 1 hit.
    PF00069. Pkinase. 1 hit.
    [Graphical view]
    SMARTiSM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS50951. SARAH. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: Q9JI10-1) [UniParc]FASTAAdd to Basket

    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

    MEQPPASKSK LKKLSEDSLT KQPEEVFDVL EKLGEGSYGS VFKAIHKESG    50
    QVVAIKQVPV ESDLQEIIKE ISIMQQCDSP YVVKYYGSYF KNTDLWIVME 100
    YCGAGSVSDI IRLRNKTLTE DEIATILKST LKGLEYLHFM RKIHRDIKAG 150
    NILLNTEGHA KLADFGVAGQ LTDTMAKRNT VIGTPFWMAP EVIQEIGYNC 200
    VADIWSLGIT SIEMAEGKPP YADIHPMRAI FMIPTNPPPT FRKPELWSDD 250
    FTDFVKKCLV KSPEQRATAT QLLQHPFIKN AKPVSILRDL IAEAMEIKAK 300
    RHEEQQRELE EEEENSDEDE LDSHTMVKTS SESVGTMRAT STMSEGAQTM 350
    IEHNSTMLES DLGTMVINSE EEEEEEEEEE EDGTMKRNAT SPQVQRPSFM 400
    DYFDKQDFKN KSHENCDQSM REPGPMSNSV FPDNWRVPQD GDFDFLKNLS 450
    LEELQMRLKA LDPMMEREIE ELHQRYSAKR QPILDAMDAK KRRQQNF 497
    Length:497
    Mass (Da):56,855
    Last modified:October 1, 2000 - v1
    Checksum:i9CDD365437581665
    GO
    Isoform 2 (identifier: Q9JI10-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         9-78: Missing.

    Note: No experimental confirmation available.

    Show »
    Length:427
    Mass (Da):49,067
    Checksum:i556176AE5A26F79E
    GO

    Sequence cautioni

    The sequence AAA75300.1 differs from that shown. Reason: Frameshift at position 432.

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei9 – 7870Missing in isoform 2. 1 PublicationVSP_020047Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF271361 mRNA. Translation: AAF75790.1.
    U28726 mRNA. Translation: AAA75300.1. Frameshift.
    AY058922 mRNA. Translation: AAL29682.1.
    BC037440 mRNA. Translation: AAH37440.1.
    BC049123 mRNA. Translation: AAH49123.2.
    CCDSiCCDS37059.1. [Q9JI10-1]
    RefSeqiNP_062609.2. NM_019635.2. [Q9JI10-1]
    UniGeneiMm.262330.

    Genome annotation databases

    EnsembliENSMUST00000018476; ENSMUSP00000018476; ENSMUSG00000022329. [Q9JI10-1]
    ENSMUST00000067033; ENSMUSP00000064225; ENSMUSG00000022329. [Q9JI10-2]
    GeneIDi56274.
    KEGGimmu:56274.
    UCSCiuc007vlz.1. mouse. [Q9JI10-1]
    uc011zrz.1. mouse. [Q9JI10-2]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF271361 mRNA. Translation: AAF75790.1 .
    U28726 mRNA. Translation: AAA75300.1 . Frameshift.
    AY058922 mRNA. Translation: AAL29682.1 .
    BC037440 mRNA. Translation: AAH37440.1 .
    BC049123 mRNA. Translation: AAH49123.2 .
    CCDSi CCDS37059.1. [Q9JI10-1 ]
    RefSeqi NP_062609.2. NM_019635.2. [Q9JI10-1 ]
    UniGenei Mm.262330.

    3D structure databases

    ProteinModelPortali Q9JI10.
    SMRi Q9JI10. Positions 10-494.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 207869. 1 interaction.
    IntActi Q9JI10. 1 interaction.

    Chemistry

    BindingDBi Q9JI10.
    ChEMBLi CHEMBL4310.

    PTM databases

    PhosphoSitei Q9JI10.

    Proteomic databases

    MaxQBi Q9JI10.
    PaxDbi Q9JI10.
    PRIDEi Q9JI10.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000018476 ; ENSMUSP00000018476 ; ENSMUSG00000022329 . [Q9JI10-1 ]
    ENSMUST00000067033 ; ENSMUSP00000064225 ; ENSMUSG00000022329 . [Q9JI10-2 ]
    GeneIDi 56274.
    KEGGi mmu:56274.
    UCSCi uc007vlz.1. mouse. [Q9JI10-1 ]
    uc011zrz.1. mouse. [Q9JI10-2 ]

    Organism-specific databases

    CTDi 6788.
    MGIi MGI:1928487. Stk3.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00640000091192.
    HOGENOMi HOG000234203.
    HOVERGENi HBG108518.
    InParanoidi Q9JI10.
    KOi K04412.
    OMAi XDEDELD.
    OrthoDBi EOG7TF79T.
    PhylomeDBi Q9JI10.
    TreeFami TF354217.

    Enzyme and pathway databases

    Reactomei REACT_196537. Signaling by Hippo.

    Miscellaneous databases

    NextBioi 312160.
    PROi Q9JI10.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q9JI10.
    Bgeei Q9JI10.
    CleanExi MM_STK3.
    Genevestigatori Q9JI10.

    Family and domain databases

    InterProi IPR011009. Kinase-like_dom.
    IPR024205. Mst1_SARAH_domain.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR011524. SARAH_dom.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    [Graphical view ]
    Pfami PF11629. Mst1_SARAH. 1 hit.
    PF00069. Pkinase. 1 hit.
    [Graphical view ]
    SMARTi SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS50951. SARAH. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation."
      Lee K.-K., Ohyama T., Yajima N., Tsubuki S., Yonehara S.
      J. Biol. Chem. 276:19276-19285(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEOLYTIC PROCESSING.
      Strain: BALB/c.
    2. Han J.
      Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
      Tissue: Liver.
    3. "Molecular cloning and characterization of mouse MST2 kinase from olfactory receptor neurons."
      de las Heras R., Mackay-Sim A., Bushell G.R.
      Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
      Tissue: Olfactory epithelium.
    4. "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] (ISOFORMS 1 AND 2).
      Strain: C57BL/6 and FVB/N.
      Tissue: Brain and Mammary gland.
    5. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-316, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Liver.
    6. "The phagosomal proteome in interferon-gamma-activated macrophages."
      Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P.
      Immunity 30:143-154(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-316, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    7. "Large scale localization of protein phosphorylation by use of electron capture dissociation mass spectrometry."
      Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.
      Mol. Cell. Proteomics 8:904-912(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Embryonic fibroblast.
    8. "Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver."
      Lu L., Li Y., Kim S.M., Bossuyt W., Liu P., Qiu Q., Wang Y., Halder G., Finegold M.J., Lee J.S., Johnson R.L.
      Proc. Natl. Acad. Sci. U.S.A. 107:1437-1442(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, DISRUPTION PHENOTYPE.

    Entry informationi

    Entry nameiSTK3_MOUSE
    AccessioniPrimary (citable) accession number: Q9JI10
    Secondary accession number(s): Q60877, Q80UG4, Q8CI58
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: April 26, 2004
    Last sequence update: October 1, 2000
    Last modified: October 1, 2014
    This is version 120 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. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3