Q64434 (PTK6_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified November 13, 2013. Version 126. History...
Names and origin
|Protein names||Recommended name:|
Protein-tyrosine kinase 6
SRC-related intestinal kinase
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||451 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
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
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
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
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
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.
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.
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
Contains 1 protein kinase domain.
Contains 1 SH2 domain.
Contains 1 SH3 domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 451||451||Protein-tyrosine kinase 6||PRO_0000088134|
|Domain||11 – 72||62||SH3|
|Domain||78 – 170||93||SH2|
|Domain||191 – 445||255||Protein kinase|
|Nucleotide binding||197 – 205||9||ATP By similarity|
|Region||171 – 190||20||Linker|
|Active site||312||1||Proton acceptor By similarity|
|Binding site||219||1||ATP By similarity|
Amino acid modifications
|Modified residue||13||1||Phosphotyrosine By similarity|
|Modified residue||61||1||Phosphotyrosine By similarity|
|Modified residue||66||1||Phosphotyrosine By similarity|
|Modified residue||114||1||Phosphotyrosine By similarity|
|Modified residue||342||1||Phosphotyrosine; by autocatalysis By similarity|
|Modified residue||351||1||Phosphotyrosine By similarity|
|Modified residue||447||1||Phosphotyrosine Probable|
|Mutagenesis||447||1||Y → F: Increase in the kinase activation level. Ref.5|
|||"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.
|||"Promoter region of the mouse sik gene."|
Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-77.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.|
|U16805 mRNA. Translation: AAA67929.1.|
AF016545 Genomic DNA. Translation: AAB94550.1.
|RefSeq||NP_033210.1. NM_009184.2. |
3D structure databases
|SMR||Q64434. Positions 1-437. |
Protein-protein interaction databases
|IntAct||Q64434. 1 interaction.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000016511; ENSMUSP00000016511; ENSMUSG00000038751. |
|UCSC||uc008olk.1. mouse. |
|MGI||MGI:99683. Ptk6. |
Enzyme and pathway databases
|BRENDA||22.214.171.124. 3474. |
Gene expression databases
Family and domain databases
|Gene3D||3.30.505.10. 1 hit. |
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF07714. Pkinase_Tyr. 1 hit. |
PF00017. SH2. 1 hit.
|PRINTS||PR00401. SH2DOMAIN. |
|SMART||SM00252. SH2. 1 hit. |
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
|SUPFAM||SSF50044. SSF50044. 1 hit. |
SSF56112. SSF56112. 1 hit.
|PROSITE||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.
|Accession||Primary (citable) accession number: Q64434|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|