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Q64434 (PTK6_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 132. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Protein-tyrosine kinase 6

EC=2.7.10.2
Alternative name(s):
SRC-related intestinal kinase
Gene names
Name:Ptk6
Synonyms:Sik
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length451 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.5 Ref.7 Ref.9

Catalytic activity

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

Enzyme regulation

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. Ref.5

Subunit structure

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. Ref.3 Ref.5

Subcellular location

Cytoplasm. Nucleus. Membrane. Cell projectionruffle By similarity. Note: Also found to be membrane-associated. Colocalizes with KHDRBS1, within the nucleus. Ref.5 Ref.6 Ref.7

Tissue specificity

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. Ref.7

Developmental stage

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. Ref.4

Domain

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.

Post-translational modification

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.

Disruption phenotype

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. Ref.8

Sequence similarities

Belongs to the protein kinase superfamily. Tyr protein kinase family. BRK/PTK6/SIK subfamily.

Contains 1 protein kinase domain.

Contains 1 SH2 domain.

Contains 1 SH3 domain.

Ontologies

Keywords
   Cellular componentCell projection
Cytoplasm
Membrane
Nucleus
   DomainSH2 domain
SH3 domain
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Transferase
Tyrosine-protein kinase
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcell migration

Inferred from electronic annotation. Source: Ensembl

cellular response to retinoic acid

Inferred from electronic annotation. Source: Ensembl

intestinal epithelial cell differentiation

Inferred from mutant phenotype Ref.8. Source: UniProtKB

negative regulation of growth

Inferred from mutant phenotype Ref.8. Source: UniProtKB

negative regulation of protein tyrosine kinase activity

Inferred from electronic annotation. Source: Ensembl

positive regulation of neuron projection development

Inferred from electronic annotation. Source: Ensembl

protein autophosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

protein phosphorylation

Inferred from direct assay PubMed 12624099. Source: MGI

tyrosine phosphorylation of Stat3 protein

Inferred from sequence or structural similarity. Source: UniProtKB

tyrosine phosphorylation of Stat5 protein

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from direct assay PubMed 12200423PubMed 12624099Ref.6. Source: MGI

plasma membrane

Inferred from electronic annotation. Source: Ensembl

ruffle

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

non-membrane spanning protein tyrosine kinase activity

Inferred from electronic annotation. Source: UniProtKB-EC

protein serine/threonine kinase activity

Inferred from direct assay PubMed 12624099. Source: MGI

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 451451Protein-tyrosine kinase 6
PRO_0000088134

Regions

Domain11 – 7262SH3
Domain78 – 17093SH2
Domain191 – 445255Protein kinase
Nucleotide binding197 – 2059ATP By similarity
Region171 – 19020Linker

Sites

Active site3121Proton acceptor By similarity
Binding site2191ATP By similarity

Amino acid modifications

Modified residue131Phosphotyrosine By similarity
Modified residue611Phosphotyrosine By similarity
Modified residue661Phosphotyrosine By similarity
Modified residue1141Phosphotyrosine By similarity
Modified residue3421Phosphotyrosine; by autocatalysis By similarity
Modified residue3511Phosphotyrosine By similarity
Modified residue4471Phosphotyrosine Probable

Experimental info

Mutagenesis4471Y → F: Increase in the kinase activation level. Ref.5

Sequences

Sequence LengthMass (Da)Tools
Q64434 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 8FBEC26025498DEC

FASTA45151,972
        10         20         30         40         50         60 
MVSWDKAHLG PKYVGLWDFK ARTDEELSFQ AGDLLHVTKK EELWWWATLL DAEGKALAEG 

        70         80         90        100        110        120 
YVPHNYLAEK ETVESEPWFF GCISRSEAMH RLQAEDNSKG AFLIRVSQKP GADYVLSVRD 

       130        140        150        160        170        180 
AQAVRHYRIW KNNEGRLHLN EAVSFSNLSE LVDYHKTQSL SHGLQLSMPC WKHKTEPLPH 

       190        200        210        220        230        240 
WDDWERPREE FTLCKKLGAG YFGEVFEALW KGQVHVAVKV ISRDNLLHQH TFQAEIQAMK 

       250        260        270        280        290        300 
KLRHKHILSL YAVATAGDPV YIITELMPKG NLLQLLRDSD EKALPILELV DFASQVAEGM 

       310        320        330        340        350        360 
CYLESQNYIH RDLAARNVLV TENNLCKVGD FGLARLVKED IYLSHEHNVP YKWTAPEALS 

       370        380        390        400        410        420 
RGHYSIKSDV WSFGVLLHEI FSRGQMPYPG MSNHETFLRV DAGYRMPCPL ECPPNIHKLM 

       430        440        450 
LSCWSRDPKQ RPCFKDLCEK LTGITRYENL V 

« Hide

References

[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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U16805 mRNA. Translation: AAA67929.1.
AF016545 Genomic DNA. Translation: AAB94550.1.
CCDSCCDS17203.1.
RefSeqNP_033210.1. NM_009184.2.
UniGeneMm.4497.

3D structure databases

ProteinModelPortalQ64434.
SMRQ64434. Positions 1-437.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActQ64434. 1 interaction.

PTM databases

PhosphoSiteQ64434.

Proteomic databases

MaxQBQ64434.
PRIDEQ64434.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000016511; ENSMUSP00000016511; ENSMUSG00000038751.
GeneID20459.
KEGGmmu:20459.
UCSCuc008olk.1. mouse.

Organism-specific databases

CTD5753.
MGIMGI:99683. Ptk6.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00640000091347.
HOGENOMHOG000233858.
HOVERGENHBG008761.
InParanoidQ64434.
KOK08894.
OMAVRHYKIW.
OrthoDBEOG73BVCD.
PhylomeDBQ64434.
TreeFamTF351634.

Enzyme and pathway databases

BRENDA2.7.10.2. 3474.

Gene expression databases

BgeeQ64434.
CleanExMM_PTK6.
GenevestigatorQ64434.

Family and domain databases

Gene3D3.30.505.10. 1 hit.
InterProIPR011009. 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]
PfamPF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF14604. SH3_9. 1 hit.
[Graphical view]
PRINTSPR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.
PR00109. TYRKINASE.
SMARTSM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF50044. SSF50044. 1 hit.
SSF55550. SSF55550. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS00107. 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]
ProtoNetSearch...

Other

NextBio298538.
PROQ64434.
SOURCESearch...

Entry information

Entry namePTK6_MOUSE
AccessionPrimary (citable) accession number: Q64434
Entry history
Integrated into UniProtKB/Swiss-Prot: December 1, 2000
Last sequence update: November 1, 1996
Last modified: July 9, 2014
This is version 132 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot