ID PTK6_MOUSE Reviewed; 451 AA.
AC Q64434;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 24-JAN-2024, entry version 193.
DE RecName: Full=Protein-tyrosine kinase 6;
DE EC=2.7.10.2;
DE AltName: Full=SRC-related intestinal kinase;
GN Name=Ptk6; Synonyms=Sik;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=BALB/cJ, and ICR; TISSUE=Intestinal crypt;
RX PubMed=7838533;
RA Vasioukhin V., Serfas M.S., Siyanova E.Y., Polonskaia M., Costigan V.J.,
RA Liu B., Thomason A., Tyner A.L.;
RT "A novel intracellular epithelial cell tyrosine kinase is expressed in the
RT skin and gastrointestinal tract.";
RL Oncogene 10:349-357(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-77.
RC STRAIN=BALB/cJ;
RA Siyanova E.Y.;
RT "Promoter region of the mouse sik gene.";
RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP INTERACTION WITH GAP-A.P65.
RX PubMed=9405638; DOI=10.1073/pnas.94.26.14477;
RA Vasioukhin V., Tyner A.L.;
RT "A role for the epithelial-cell-specific tyrosine kinase Sik during
RT keratinocyte differentiation.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:14477-14482(1997).
RN [4]
RP DEVELOPMENTAL STAGE.
RX PubMed=10430081;
RA Llor X., Serfas M.S., Bie W., Vasioukhin V., Polonskaia M., Derry J.,
RA Abbott C.M., Tyner A.L.;
RT "BRK/Sik expression in the gastrointestinal tract and in colon tumors.";
RL Clin. Cancer Res. 5:1767-1777(1999).
RN [5]
RP INTERACTION WITH KHDRBS1, MUTAGENESIS OF TYR-447, SUBCELLULAR LOCATION,
RP ACTIVITY REGULATION, AND FUNCTION IN PHOSPHORYLATION OF KHDRBS1.
RX PubMed=10913193; DOI=10.1128/mcb.20.16.6114-6126.2000;
RA Derry J.J., Richard S., Valderrama Carvajal H., Ye X., Vasioukhin V.,
RA Cochrane A.W., Chen T., Tyner A.L.;
RT "Sik (BRK) phosphorylates Sam68 in the nucleus and negatively regulates its
RT RNA binding ability.";
RL Mol. Cell. Biol. 20:6114-6126(2000).
RN [6]
RP SUBCELLULAR LOCATION.
RX PubMed=12833144; DOI=10.1038/sj.onc.1206465;
RA Derry J.J., Prins G.S., Ray V., Tyner A.L.;
RT "Altered localization and activity of the intracellular tyrosine kinase
RT BRK/Sik in prostate tumor cells.";
RL Oncogene 22:4212-4220(2003).
RN [7]
RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=15471878; DOI=10.1074/jbc.m409579200;
RA Haegebarth A., Heap D., Bie W., Derry J.J., Richard S., Tyner A.L.;
RT "The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-
RT binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2.";
RL J. Biol. Chem. 279:54398-54404(2004).
RN [8]
RP DISRUPTION PHENOTYPE.
RX PubMed=16782882; DOI=10.1128/mcb.01901-05;
RA Haegebarth A., Bie W., Yang R., Crawford S.E., Vasioukhin V., Fuchs E.,
RA Tyner A.L.;
RT "Protein tyrosine kinase 6 negatively regulates growth and promotes
RT enterocyte differentiation in the small intestine.";
RL Mol. Cell. Biol. 26:4949-4957(2006).
RN [9]
RP FUNCTION IN APOPTOSIS.
RX PubMed=19501589; DOI=10.1053/j.gastro.2009.05.054;
RA Haegebarth A., Perekatt A.O., Bie W., Gierut J.J., Tyner A.L.;
RT "Induction of protein tyrosine kinase 6 in mouse intestinal crypt
RT epithelial cells promotes DNA damage-induced apoptosis.";
RL Gastroenterology 137:945-954(2009).
CC -!- FUNCTION: Non-receptor tyrosine-protein kinase implicated in the
CC regulation of a variety of signaling pathways that control the
CC differentiation and maintenance of normal epithelia, as well as tumor
CC growth. Function seems to be context dependent and differ depending on
CC cell type, as well as its intracellular localization. A number of
CC potential nuclear and cytoplasmic substrates have been identified.
CC These include the RNA-binding proteins: KHDRBS1/SAM68, KHDRBS2/SLM1,
CC KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: STAT3 and STAT5A/B
CC and a variety of signaling molecules: ARHGAP35/p190RhoGAP,
CC PXN/paxillin, BTK/ATK, STAP2/BKS. Associates also with a variety of
CC proteins that are likely upstream of PTK6 in various signaling
CC pathways, or for which PTK6 may play an adapter-like role. These
CC proteins include ADAM15, EGFR, ERBB2, ERBB3 and IRS4. In normal or non-
CC tumorigenic tissues, PTK6 promotes cellular differentiation and
CC apoptosis. In tumors PTK6 contributes to cancer progression by
CC sensitizing cells to mitogenic signals and enhancing proliferation,
CC anchorage-independent survival and migration/invasion. Association with
CC EGFR, ERBB2, ERBB3 may contribute to mammary tumor development and
CC growth through enhancement of EGF-induced signaling via BTK/AKT and PI3
CC kinase. Contributes to migration and proliferation by contributing to
CC EGF-mediated phosphorylation of ARHGAP35/p190RhoGAP, which promotes
CC association with RASA1/p120RasGAP, inactivating RhoA while activating
CC RAS. EGF stimulation resulted in phosphorylation of PNX/Paxillin by
CC PTK6 and activation of RAC1 via CRK/CrKII, thereby promoting migration
CC and invasion. PTK6 activates STAT3 and STAT5B to promote proliferation.
CC Nuclear PTK6 may be important for regulating growth in normal
CC epithelia, while cytoplasmic PTK6 might activate oncogenic signaling
CC pathways. {ECO:0000269|PubMed:10913193, ECO:0000269|PubMed:15471878,
CC ECO:0000269|PubMed:19501589}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- ACTIVITY REGULATION: Activated by EGF, NRG1 and IGF1. Inhibited by
CC SOCS3 to phosphorylate STAT3. Stabilized in the inactive form by an
CC association between the SH3 domain and the SH2-TK linker region.
CC Interaction between Trp-184 within SH2-TK linker region and the
CC catalytic domain appears essential for positive regulation of kinase
CC activity. {ECO:0000269|PubMed:10913193}.
CC -!- SUBUNIT: Interacts with KHDRBS1. Interacts with phosphorylated IRS4 (By
CC similarity). Interacts with GAP-A.p65. Interacts with ADAM15 (By
CC similarity). Interacts (via SH3 and SH2 domains) with phosphorylated
CC IRS4 (By similarity). Interacts (via SH3 domain) with SFPQ (By
CC similarity). Interacts with EGFR and ERBB2 (By similarity). Interacts
CC with STAP2 (By similarity). Interacts with PNX (By similarity).
CC Interacts with SFPQ (By similarity). Interacts with PTK/ATK (By
CC similarity). Interacts with CTNNB1 (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Membrane. Cell projection,
CC ruffle {ECO:0000250}. Note=Also found to be membrane-associated.
CC Colocalizes with KHDRBS1, within the nucleus.
CC -!- TISSUE SPECIFICITY: Expressed only in epithelial tissues, including the
CC skin and lining of the alimentary canal. Restricted to the cell layers
CC immediately above the proliferative cell zone in these epithelia.
CC {ECO:0000269|PubMed:15471878}.
CC -!- DEVELOPMENTAL STAGE: First detected at day 15.5 of gestation in the
CC embryo, where it is expressed in the newly forming granular layer of
CC the skin. Is found in stomach at day 17.5.
CC {ECO:0000269|PubMed:10430081}.
CC -!- DOMAIN: The SH3 domain plays a major role in substrate interactions.
CC The SH2 domain of PTK6 plays a role in protein-protein interactions,
CC but is likely more important for the regulation of catalytic activity
CC (By similarity). {ECO:0000250}.
CC -!- PTM: Autophosphorylated. Autophosphorylation of Tyr-342 leads to an
CC increase of kinase activity. Tyr-447 binds to the SH2 domain when
CC phosphorylated and negatively regulates kinase activity (By
CC similarity). {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Deficient mice have an increased cell turnover in
CC the small intestine, which is accompanied by increased villus length
CC and crypt depth and delayed enterocyte differentiation that is
CC accompanied by increased PTK/AKT and WNT signaling.
CC {ECO:0000269|PubMed:16782882}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. BRK/PTK6/SIK subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; U16805; AAA67929.1; -; mRNA.
DR EMBL; AF016545; AAB94550.1; -; Genomic_DNA.
DR CCDS; CCDS17203.1; -.
DR RefSeq; NP_033210.1; NM_009184.2.
DR AlphaFoldDB; Q64434; -.
DR SMR; Q64434; -.
DR BioGRID; 203249; 2.
DR IntAct; Q64434; 1.
DR MINT; Q64434; -.
DR STRING; 10090.ENSMUSP00000016511; -.
DR iPTMnet; Q64434; -.
DR PhosphoSitePlus; Q64434; -.
DR MaxQB; Q64434; -.
DR PaxDb; 10090-ENSMUSP00000016511; -.
DR ProteomicsDB; 301933; -.
DR Antibodypedia; 29774; 629 antibodies from 38 providers.
DR DNASU; 20459; -.
DR Ensembl; ENSMUST00000016511.6; ENSMUSP00000016511.6; ENSMUSG00000038751.6.
DR GeneID; 20459; -.
DR KEGG; mmu:20459; -.
DR UCSC; uc008olk.1; mouse.
DR AGR; MGI:99683; -.
DR CTD; 5753; -.
DR MGI; MGI:99683; Ptk6.
DR VEuPathDB; HostDB:ENSMUSG00000038751; -.
DR eggNOG; KOG0197; Eukaryota.
DR GeneTree; ENSGT00940000161218; -.
DR HOGENOM; CLU_000288_7_2_1; -.
DR InParanoid; Q64434; -.
DR OMA; LWKGQVR; -.
DR OrthoDB; 1614410at2759; -.
DR PhylomeDB; Q64434; -.
DR TreeFam; TF351634; -.
DR BRENDA; 2.7.10.2; 3474.
DR Reactome; R-MMU-187577; SCF(Skp2)-mediated degradation of p27/p21.
DR Reactome; R-MMU-69231; Cyclin D associated events in G1.
DR Reactome; R-MMU-8847993; ERBB2 Activates PTK6 Signaling.
DR Reactome; R-MMU-8849468; PTK6 Regulates Proteins Involved in RNA Processing.
DR Reactome; R-MMU-8849469; PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1.
DR Reactome; R-MMU-8849470; PTK6 Regulates Cell Cycle.
DR Reactome; R-MMU-8849471; PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases.
DR Reactome; R-MMU-8849472; PTK6 Down-Regulation.
DR Reactome; R-MMU-8849474; PTK6 Activates STAT3.
DR Reactome; R-MMU-8857538; PTK6 promotes HIF1A stabilization.
DR BioGRID-ORCS; 20459; 1 hit in 79 CRISPR screens.
DR ChiTaRS; Nop58; mouse.
DR PRO; PR:Q64434; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q64434; Protein.
DR Bgee; ENSMUSG00000038751; Expressed in jejunum and 38 other cell types or tissues.
DR ExpressionAtlas; Q64434; baseline and differential.
DR Genevisible; Q64434; MM.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0031234; C:extrinsic component of cytoplasmic side of plasma membrane; IBA:GO_Central.
DR GO; GO:0016604; C:nuclear body; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0001726; C:ruffle; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; ISO:MGI.
DR GO; GO:0004713; F:protein tyrosine kinase activity; ISO:MGI.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0016477; P:cell migration; ISO:MGI.
DR GO; GO:0071300; P:cellular response to retinoic acid; ISO:MGI.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:0060575; P:intestinal epithelial cell differentiation; IMP:UniProtKB.
DR GO; GO:0045926; P:negative regulation of growth; IMP:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISO:MGI.
DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR GO; GO:0007260; P:tyrosine phosphorylation of STAT protein; ISS:UniProtKB.
DR CDD; cd10358; SH2_PTK6_Brk; 1.
DR Gene3D; 3.30.505.10; SH2 domain; 1.
DR Gene3D; 2.30.30.40; SH3 Domains; 1.
DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR035846; PTK6_SH2.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR PANTHER; PTHR24418:SF265; PROTEIN-TYROSINE KINASE 6; 1.
DR PANTHER; PTHR24418; TYROSINE-PROTEIN KINASE; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF00017; SH2; 1.
DR Pfam; PF00018; SH3_1; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR PRINTS; PR00452; SH3DOMAIN.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00252; SH2; 1.
DR SMART; SM00326; SH3; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR SUPFAM; SSF55550; SH2 domain; 1.
DR SUPFAM; SSF50044; SH3-domain; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS50001; SH2; 1.
DR PROSITE; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell projection; Cytoplasm; Kinase; Membrane;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW SH2 domain; SH3 domain; Transferase; Tyrosine-protein kinase.
FT CHAIN 1..451
FT /note="Protein-tyrosine kinase 6"
FT /id="PRO_0000088134"
FT DOMAIN 8..72
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 78..170
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT DOMAIN 191..445
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 171..190
FT /note="Linker"
FT ACT_SITE 312
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 197..205
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 219
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 13
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13882"
FT MOD_RES 61
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13882"
FT MOD_RES 66
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13882"
FT MOD_RES 114
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13882"
FT MOD_RES 342
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q13882"
FT MOD_RES 351
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13882"
FT MOD_RES 447
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13882, ECO:0000305"
FT MUTAGEN 447
FT /note="Y->F: Increase in the kinase activation level."
FT /evidence="ECO:0000269|PubMed:10913193"
SQ SEQUENCE 451 AA; 51972 MW; 8FBEC26025498DEC CRC64;
MVSWDKAHLG PKYVGLWDFK ARTDEELSFQ AGDLLHVTKK EELWWWATLL DAEGKALAEG
YVPHNYLAEK ETVESEPWFF GCISRSEAMH RLQAEDNSKG AFLIRVSQKP GADYVLSVRD
AQAVRHYRIW KNNEGRLHLN EAVSFSNLSE LVDYHKTQSL SHGLQLSMPC WKHKTEPLPH
WDDWERPREE FTLCKKLGAG YFGEVFEALW KGQVHVAVKV ISRDNLLHQH TFQAEIQAMK
KLRHKHILSL YAVATAGDPV YIITELMPKG NLLQLLRDSD EKALPILELV DFASQVAEGM
CYLESQNYIH RDLAARNVLV TENNLCKVGD FGLARLVKED IYLSHEHNVP YKWTAPEALS
RGHYSIKSDV WSFGVLLHEI FSRGQMPYPG MSNHETFLRV DAGYRMPCPL ECPPNIHKLM
LSCWSRDPKQ RPCFKDLCEK LTGITRYENL V
//
