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Q64434

- PTK6_MOUSE

UniProt

Q64434 - PTK6_MOUSE

Protein

Protein-tyrosine kinase 6

Gene

Ptk6

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 133 (01 Oct 2014)
      Sequence version 1 (01 Nov 1996)
      Previous versions | rss
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    Functioni

    Non-receptor tyrosine-protein kinase implicated in the regulation of a variety of signaling pathways that control the differentiation and maintenance of normal epithelia, as well as tumor growth. Function seems to be context dependent and differ depending on cell type, as well as its intracellular localization. A number of potential nuclear and cytoplasmic substrates have been identified. These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B and a variety of signaling molecules: ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Associates also with a variety of proteins that are likely upstream of PTK6 in various signaling pathways, or for which PTK6 may play an adapter-like role. These proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 promotes cellular differentiation and apoptosis. In tumors PTK6 contributes to cancer progression by sensitizing cells to mitogenic signals and enhancing proliferation, anchorage-independent survival and migration/invasion. Association with EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and growth through enhancement of EGF-induced signaling via BTK/AKT and PI3 kinase. Contributes to migration and proliferation by contributing to EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes association with RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation. Nuclear PTK6 may be important for regulating growth in normal epithelia, while cytoplasmic PTK6 might activate oncogenic signaling pathways.3 Publications

    Catalytic activityi

    ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

    Enzyme regulationi

    Activated by EGF, NRG1 and IGF1. Inhibited by SOCS3 to phosphorylate STAT3. Stabilized in the inactive form by an association between the SH3 domain and the SH2-TK linker region. Interaction between Trp-184 within SH2-TK linker region and the catalytic domain appears essential for positive regulation of kinase activity.1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei219 – 2191ATPPROSITE-ProRule annotation
    Active sitei312 – 3121Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi197 – 2059ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. non-membrane spanning protein tyrosine kinase activity Source: UniProtKB-EC

    GO - Biological processi

    1. cell migration Source: Ensembl
    2. cellular response to retinoic acid Source: Ensembl
    3. intestinal epithelial cell differentiation Source: UniProtKB
    4. negative regulation of growth Source: UniProtKB
    5. negative regulation of protein tyrosine kinase activity Source: Ensembl
    6. positive regulation of neuron projection development Source: Ensembl
    7. protein autophosphorylation Source: UniProtKB
    8. tyrosine phosphorylation of Stat3 protein Source: UniProtKB
    9. tyrosine phosphorylation of Stat5 protein Source: UniProtKB

    Keywords - Molecular functioni

    Kinase, Transferase, Tyrosine-protein kinase

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.10.2. 3474.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Protein-tyrosine kinase 6 (EC:2.7.10.2)
    Alternative name(s):
    SRC-related intestinal kinase
    Gene namesi
    Name:Ptk6
    Synonyms:Sik
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 2

    Organism-specific databases

    MGIiMGI:99683. Ptk6.

    Subcellular locationi

    Cytoplasm. Nucleus. Membrane. Cell projectionruffle By similarity
    Note: Also found to be membrane-associated. Colocalizes with KHDRBS1, within the nucleus.

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB-SubCell
    2. nucleus Source: MGI
    3. plasma membrane Source: Ensembl
    4. ruffle Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Cell projection, Cytoplasm, Membrane, Nucleus

    Pathology & Biotechi

    Disruption phenotypei

    Deficient mice have an increased cell turnover in the small intestine, which is accompanied by increased villus length and crypt depth and delayed enterocyte differentiation that is accompanied by increased PTK/AKT and WNT signaling.1 Publication

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi447 – 4471Y → F: Increase in the kinase activation level. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 451451Protein-tyrosine kinase 6PRO_0000088134Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei13 – 131PhosphotyrosineBy similarity
    Modified residuei61 – 611PhosphotyrosineBy similarity
    Modified residuei66 – 661PhosphotyrosineBy similarity
    Modified residuei114 – 1141PhosphotyrosineBy similarity
    Modified residuei342 – 3421Phosphotyrosine; by autocatalysisBy similarity
    Modified residuei351 – 3511PhosphotyrosineBy similarity
    Modified residuei447 – 4471PhosphotyrosineCurated

    Post-translational modificationi

    Autophosphorylated. Autophosphorylation of Tyr-342 leads to an increase of kinase activity. Tyr-447 binds to the SH2 domain when phosphorylated and negatively regulates kinase activity By similarity.By similarity

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    MaxQBiQ64434.
    PRIDEiQ64434.

    PTM databases

    PhosphoSiteiQ64434.

    Expressioni

    Tissue specificityi

    Expressed only in epithelial tissues, including the skin and lining of the alimentary canal. Restricted to the cell layers immediately above the proliferative cell zone in these epithelia.1 Publication

    Developmental stagei

    First detected at day 15.5 of gestation in the embryo, where it is expressed in the newly forming granular layer of the skin. Is found in stomach at day 17.5.1 Publication

    Gene expression databases

    BgeeiQ64434.
    CleanExiMM_PTK6.
    GenevestigatoriQ64434.

    Interactioni

    Subunit structurei

    Interacts with KHDRBS1. Interacts with phosphorylated IRS4 By similarity. Interacts with GAP-A.p65. Interacts with ADAM15 By similarity. Interacts (via SH3 and SH2 domains) with phosphorylated IRS4 By similarity. Interacts (via SH3 domain) with SFPQ By similarity. Interacts with EGFR and ERBB2 By similarity. Interacts with STAP2 By similarity. Interacts with PNX By similarity. Interacts with SFPQ By similarity. Interacts with PTK/ATK By similarity. Interacts with CTNNB1 By similarity.By similarity

    Protein-protein interaction databases

    IntActiQ64434. 1 interaction.

    Structurei

    3D structure databases

    ProteinModelPortaliQ64434.
    SMRiQ64434. Positions 1-437.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini11 – 7262SH3PROSITE-ProRule annotationAdd
    BLAST
    Domaini78 – 17093SH2PROSITE-ProRule annotationAdd
    BLAST
    Domaini191 – 445255Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni171 – 19020LinkerAdd
    BLAST

    Domaini

    The SH3 domain plays a major role in substrate interactions. The SH2 domain of PTK6 plays a role in protein-protein interactions, but is likely more important for the regulation of catalytic activity By similarity.By similarity

    Sequence similaritiesi

    Belongs to the protein kinase superfamily. Tyr protein kinase family. BRK/PTK6/SIK subfamily.PROSITE-ProRule annotation
    Contains 1 protein kinase domain.PROSITE-ProRule annotation
    Contains 1 SH2 domain.PROSITE-ProRule annotation
    Contains 1 SH3 domain.PROSITE-ProRule annotation

    Keywords - Domaini

    SH2 domain, SH3 domain

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00640000091347.
    HOGENOMiHOG000233858.
    HOVERGENiHBG008761.
    InParanoidiQ64434.
    KOiK08894.
    OMAiVRHYKIW.
    OrthoDBiEOG73BVCD.
    PhylomeDBiQ64434.
    TreeFamiTF351634.

    Family and domain databases

    Gene3Di3.30.505.10. 1 hit.
    InterProiIPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
    IPR000980. SH2.
    IPR001452. SH3_domain.
    IPR008266. Tyr_kinase_AS.
    IPR020635. Tyr_kinase_cat_dom.
    [Graphical view]
    PfamiPF07714. Pkinase_Tyr. 1 hit.
    PF00017. SH2. 1 hit.
    PF14604. SH3_9. 1 hit.
    [Graphical view]
    PRINTSiPR00401. SH2DOMAIN.
    PR00452. SH3DOMAIN.
    PR00109. TYRKINASE.
    SMARTiSM00252. SH2. 1 hit.
    SM00326. SH3. 1 hit.
    SM00219. TyrKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF50044. SSF50044. 1 hit.
    SSF55550. SSF55550. 1 hit.
    SSF56112. SSF56112. 1 hit.
    PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00109. PROTEIN_KINASE_TYR. 1 hit.
    PS50001. SH2. 1 hit.
    PS50002. SH3. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q64434-1 [UniParc]FASTAAdd to Basket

    « Hide

    MVSWDKAHLG PKYVGLWDFK ARTDEELSFQ AGDLLHVTKK EELWWWATLL    50
    DAEGKALAEG YVPHNYLAEK ETVESEPWFF GCISRSEAMH RLQAEDNSKG 100
    AFLIRVSQKP GADYVLSVRD AQAVRHYRIW KNNEGRLHLN EAVSFSNLSE 150
    LVDYHKTQSL SHGLQLSMPC WKHKTEPLPH WDDWERPREE FTLCKKLGAG 200
    YFGEVFEALW KGQVHVAVKV ISRDNLLHQH TFQAEIQAMK KLRHKHILSL 250
    YAVATAGDPV YIITELMPKG NLLQLLRDSD EKALPILELV DFASQVAEGM 300
    CYLESQNYIH RDLAARNVLV TENNLCKVGD FGLARLVKED IYLSHEHNVP 350
    YKWTAPEALS RGHYSIKSDV WSFGVLLHEI FSRGQMPYPG MSNHETFLRV 400
    DAGYRMPCPL ECPPNIHKLM LSCWSRDPKQ RPCFKDLCEK LTGITRYENL 450
    V 451
    Length:451
    Mass (Da):51,972
    Last modified:November 1, 1996 - v1
    Checksum:i8FBEC26025498DEC
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U16805 mRNA. Translation: AAA67929.1.
    AF016545 Genomic DNA. Translation: AAB94550.1.
    CCDSiCCDS17203.1.
    RefSeqiNP_033210.1. NM_009184.2.
    UniGeneiMm.4497.

    Genome annotation databases

    EnsembliENSMUST00000016511; ENSMUSP00000016511; ENSMUSG00000038751.
    GeneIDi20459.
    KEGGimmu:20459.
    UCSCiuc008olk.1. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U16805 mRNA. Translation: AAA67929.1 .
    AF016545 Genomic DNA. Translation: AAB94550.1 .
    CCDSi CCDS17203.1.
    RefSeqi NP_033210.1. NM_009184.2.
    UniGenei Mm.4497.

    3D structure databases

    ProteinModelPortali Q64434.
    SMRi Q64434. Positions 1-437.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    IntActi Q64434. 1 interaction.

    PTM databases

    PhosphoSitei Q64434.

    Proteomic databases

    MaxQBi Q64434.
    PRIDEi Q64434.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000016511 ; ENSMUSP00000016511 ; ENSMUSG00000038751 .
    GeneIDi 20459.
    KEGGi mmu:20459.
    UCSCi uc008olk.1. mouse.

    Organism-specific databases

    CTDi 5753.
    MGIi MGI:99683. Ptk6.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00640000091347.
    HOGENOMi HOG000233858.
    HOVERGENi HBG008761.
    InParanoidi Q64434.
    KOi K08894.
    OMAi VRHYKIW.
    OrthoDBi EOG73BVCD.
    PhylomeDBi Q64434.
    TreeFami TF351634.

    Enzyme and pathway databases

    BRENDAi 2.7.10.2. 3474.

    Miscellaneous databases

    NextBioi 298538.
    PROi Q64434.
    SOURCEi Search...

    Gene expression databases

    Bgeei Q64434.
    CleanExi MM_PTK6.
    Genevestigatori Q64434.

    Family and domain databases

    Gene3Di 3.30.505.10. 1 hit.
    InterProi IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
    IPR000980. SH2.
    IPR001452. SH3_domain.
    IPR008266. Tyr_kinase_AS.
    IPR020635. Tyr_kinase_cat_dom.
    [Graphical view ]
    Pfami PF07714. Pkinase_Tyr. 1 hit.
    PF00017. SH2. 1 hit.
    PF14604. SH3_9. 1 hit.
    [Graphical view ]
    PRINTSi PR00401. SH2DOMAIN.
    PR00452. SH3DOMAIN.
    PR00109. TYRKINASE.
    SMARTi SM00252. SH2. 1 hit.
    SM00326. SH3. 1 hit.
    SM00219. TyrKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF50044. SSF50044. 1 hit.
    SSF55550. SSF55550. 1 hit.
    SSF56112. SSF56112. 1 hit.
    PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00109. PROTEIN_KINASE_TYR. 1 hit.
    PS50001. SH2. 1 hit.
    PS50002. SH3. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "A novel intracellular epithelial cell tyrosine kinase is expressed in the skin and gastrointestinal tract."
      Vasioukhin V., Serfas M.S., Siyanova E.Y., Polonskaia M., Costigan V.J., Liu B., Thomason A., Tyner A.L.
      Oncogene 10:349-357(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Strain: BALB/c and ICR.
      Tissue: Intestinal crypt.
    2. "Promoter region of the mouse sik gene."
      Siyanova E.Y.
      Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-77.
      Strain: BALB/c.
    3. "A role for the epithelial-cell-specific tyrosine kinase Sik during keratinocyte differentiation."
      Vasioukhin V., Tyner A.L.
      Proc. Natl. Acad. Sci. U.S.A. 94:14477-14482(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH GAP-A.P65.
    4. "BRK/Sik expression in the gastrointestinal tract and in colon tumors."
      Llor X., Serfas M.S., Bie W., Vasioukhin V., Polonskaia M., Derry J., Abbott C.M., Tyner A.L.
      Clin. Cancer Res. 5:1767-1777(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: DEVELOPMENTAL STAGE.
    5. "Sik (BRK) phosphorylates Sam68 in the nucleus and negatively regulates its RNA binding ability."
      Derry J.J., Richard S., Valderrama Carvajal H., Ye X., Vasioukhin V., Cochrane A.W., Chen T., Tyner A.L.
      Mol. Cell. Biol. 20:6114-6126(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH KHDRBS1, MUTAGENESIS OF TYR-447, SUBCELLULAR LOCATION, ENZYME REGULATION, FUNCTION IN PHOSPHORYLATION OF KHDRBS1.
    6. "Altered localization and activity of the intracellular tyrosine kinase BRK/Sik in prostate tumor cells."
      Derry J.J., Prins G.S., Ray V., Tyner A.L.
      Oncogene 22:4212-4220(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION.
    7. "The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2."
      Haegebarth A., Heap D., Bie W., Derry J.J., Richard S., Tyner A.L.
      J. Biol. Chem. 279:54398-54404(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION, FUNCTION.
    8. "Protein tyrosine kinase 6 negatively regulates growth and promotes enterocyte differentiation in the small intestine."
      Haegebarth A., Bie W., Yang R., Crawford S.E., Vasioukhin V., Fuchs E., Tyner A.L.
      Mol. Cell. Biol. 26:4949-4957(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE.
    9. "Induction of protein tyrosine kinase 6 in mouse intestinal crypt epithelial cells promotes DNA damage-induced apoptosis."
      Haegebarth A., Perekatt A.O., Bie W., Gierut J.J., Tyner A.L.
      Gastroenterology 137:945-954(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN APOPTOSIS.

    Entry informationi

    Entry nameiPTK6_MOUSE
    AccessioniPrimary (citable) accession number: Q64434
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 1, 2000
    Last sequence update: November 1, 1996
    Last modified: October 1, 2014
    This is version 133 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