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Q64434

- PTK6_MOUSE

UniProt

Q64434 - PTK6_MOUSE

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Protein

Protein-tyrosine kinase 6

Gene

Ptk6

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

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
Complete GO annotation...

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-KW
  2. membrane Source: UniProtKB-KW
  3. nucleus Source: MGI
  4. ruffle Source: Ensembl
Complete GO annotation...

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.
ExpressionAtlasiQ64434. baseline and differential.
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.
GeneTreeiENSGT00760000118938.
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

        10         20         30         40         50
MVSWDKAHLG PKYVGLWDFK ARTDEELSFQ AGDLLHVTKK EELWWWATLL
60 70 80 90 100
DAEGKALAEG YVPHNYLAEK ETVESEPWFF GCISRSEAMH RLQAEDNSKG
110 120 130 140 150
AFLIRVSQKP GADYVLSVRD AQAVRHYRIW KNNEGRLHLN EAVSFSNLSE
160 170 180 190 200
LVDYHKTQSL SHGLQLSMPC WKHKTEPLPH WDDWERPREE FTLCKKLGAG
210 220 230 240 250
YFGEVFEALW KGQVHVAVKV ISRDNLLHQH TFQAEIQAMK KLRHKHILSL
260 270 280 290 300
YAVATAGDPV YIITELMPKG NLLQLLRDSD EKALPILELV DFASQVAEGM
310 320 330 340 350
CYLESQNYIH RDLAARNVLV TENNLCKVGD FGLARLVKED IYLSHEHNVP
360 370 380 390 400
YKWTAPEALS RGHYSIKSDV WSFGVLLHEI FSRGQMPYPG MSNHETFLRV
410 420 430 440 450
DAGYRMPCPL ECPPNIHKLM LSCWSRDPKQ RPCFKDLCEK LTGITRYENL

V
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 ENSGT00760000118938.
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.
ExpressionAtlasi Q64434. baseline and differential.
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 29, 2014
This is version 134 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