ID PTK6_HUMAN Reviewed; 451 AA. AC Q13882; B2RCR3; B4DW46; Q58F01; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 07-JAN-2015, entry version 159. DE RecName: Full=Protein-tyrosine kinase 6; DE EC=2.7.10.2; DE AltName: Full=Breast tumor kinase; DE AltName: Full=Tyrosine-protein kinase BRK; GN Name=PTK6; Synonyms=BRK; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Mammary tumor; RX PubMed=8036022; RA Mitchell P.J., Barker K.T., Martindale J.E., Kamalati T., Lowe P.N., RA Page M.J., Gusterson B.A., Crompton M.R.; RT "Cloning and characterisation of cDNAs encoding a novel non-receptor RT tyrosine kinase, brk, expressed in human breast tumours."; RL Oncogene 9:2383-2390(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). RX PubMed=9333026; DOI=10.1038/sj.onc.1201292; RA Mitchell P.J., Barker K.T., Shipley J., Crompton M.R.; RT "Characterisation and chromosome mapping of the human non receptor RT tyrosine kinase gene, brk."; RL Oncogene 15:1497-1502(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Melanocyte; RX PubMed=9749526; RA Lee H.-Y., Kim M., Lee K.-H., Kang K.-N., Lee S.-T.; RT "Exon-intron structure of the human PTK6 gene demonstrates that PTK6 RT constitutes a distinct family of non-receptor tyrosine kinase."; RL Mol. Cells 8:401-407(1998). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Urinary bladder; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., RA Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Blood; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP CHARACTERIZATION, INTERACTION WITH EGFR, AND MUTAGENESIS OF LYS-219 RP AND TYR-447. RX PubMed=8940083; DOI=10.1074/jbc.271.48.30956; RA Kamalati T., Jolin H.E., Mitchell P.J., Barker K.T., Jackson L.E., RA Dean C.J., Page M.J., Gusterson B.A., Crompton M.R.; RT "Brk, a breast tumor-derived non-receptor protein-tyrosine kinase, RT sensitizes mammary epithelial cells to epidermal growth factor."; RL J. Biol. Chem. 271:30956-30963(1996). RN [8] RP TISSUE SPECIFICITY. RX PubMed=9185712; RX DOI=10.1002/(SICI)1097-0215(19970611)71:6<1061::AID-IJC24>3.0.CO;2-F; RA Easty D.J., Mitchell P.J., Patel K., Florenes V.A., Spritz R.A., RA Bennett D.C.; RT "Loss of expression of receptor tyrosine kinase family genes PTK7 and RT SEK in metastatic melanoma."; RL Int. J. Cancer 71:1061-1065(1997). RN [9] RP FUNCTION, INTERACTION WITH STAP2, AND MUTAGENESIS OF TRP-44; TYR-66; RP ARG-105 AND LYS-219. RX PubMed=10980601; DOI=10.1038/sj.onc.1203775; RA Mitchell P.J., Sara E.A., Crompton M.R.; RT "A novel adaptor-like protein which is a substrate for the non- RT receptor tyrosine kinase, BRK."; RL Oncogene 19:4273-4282(2000). RN [10] RP SUBCELLULAR LOCATION, AND INTERACTION WITH 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 RT regulates its RNA binding ability."; RL Mol. Cell. Biol. 20:6114-6126(2000). RN [11] RP PHOSPHORYLATION AT TYR-342; TYR-351 AND TYR-447, BIOPHYSICOCHEMICAL RP PROPERTIES, MUTAGENESIS OF TYR-342 AND TYR-447, ENZYME REGULATION, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=12121988; DOI=10.1074/jbc.M203877200; RA Qiu H., Miller W.T.; RT "Regulation of the nonreceptor tyrosine kinase Brk by RT autophosphorylation and by autoinhibition."; RL J. Biol. Chem. 277:34634-34641(2002). RN [12] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. 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 RT kinase BRK/Sik in prostate tumor cells."; RL Oncogene 22:4212-4220(2003). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-219 AND TYR-447, RP AND PHOSPHORYLATION. 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 RT RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and RT SLM-2."; RL J. Biol. Chem. 279:54398-54404(2004). RN [14] RP FUNCTION IN CELL MIGRATION, FUNCTION IN PHOSPHORYLATION OF PXN, RP SUBCELLULAR LOCATION, AND INTERACTION WITH PXN. RX PubMed=15572663; DOI=10.1128/MCB.24.24.10558-10572.2004; RA Chen H.Y., Shen C.H., Tsai Y.T., Lin F.C., Huang Y.P., Chen R.H.; RT "Brk activates rac1 and promotes cell migration and invasion by RT phosphorylating paxillin."; RL Mol. Cell. Biol. 24:10558-10572(2004). RN [15] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=15509496; DOI=10.1016/j.oraloncology.2004.05.010; RA Petro B.J., Tan R.C., Tyner A.L., Lingen M.W., Watanabe K.; RT "Differential expression of the non-receptor tyrosine kinase BRK in RT oral squamous cell carcinoma and normal oral epithelium."; RL Oral Oncol. 40:1040-1047(2004). RN [16] RP FUNCTION IN PHOSPHORYLATION OF BTK, AND INTERACTION WITH BTK. RX PubMed=15539407; DOI=10.1074/jbc.M412038200; RA Zhang P., Ostrander J.H., Faivre E.J., Olsen A., Fitzsimmons D., RA Lange C.A.; RT "Regulated association of protein kinase B/Akt with breast tumor RT kinase."; RL J. Biol. Chem. 280:1982-1991(2005). RN [17] RP MUTAGENESIS OF TRP-184, AND ENZYME REGULATION. RX PubMed=15961400; DOI=10.1074/jbc.M504568200; RA Kim H.I.E., Lee S.T.; RT "An intramolecular interaction between SH2-kinase linker and kinase RT domain is essential for the catalytic activity of protein-tyrosine RT kinase-6."; RL J. Biol. Chem. 280:28973-28980(2005). RN [18] RP FUNCTION IN PHOSPHORYLATION OF KHDRBS1. RX PubMed=16179349; DOI=10.1074/jbc.M505802200; RA Lukong K.E., Larocque D., Tyner A.L., Richard S.; RT "Tyrosine phosphorylation of sam68 by breast tumor kinase regulates RT intranuclear localization and cell cycle progression."; RL J. Biol. Chem. 280:38639-38647(2005). RN [19] RP INTERACTION WITH IRS4, AND ENZYME REGULATION. RX PubMed=15870689; DOI=10.1038/sj.onc.1208721; RA Qiu H., Zappacosta F., Su W., Annan R.S., Miller W.T.; RT "Interaction between Brk kinase and insulin receptor substrate-4."; RL Oncogene 24:5656-5664(2005). RN [20] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=16651629; DOI=10.2353/ajpath.2006.050521; RA Kasprzycka M., Majewski M., Wang Z.J., Ptasznik A., Wysocka M., RA Zhang Q., Marzec M., Gimotty P., Crompton M.R., Wasik M.A.; RT "Expression and oncogenic role of Brk (PTK6/Sik) protein tyrosine RT kinase in lymphocytes."; RL Am. J. Pathol. 168:1631-1641(2006). RN [21] RP FUNCTION IN PHOSPHORYLATION OF STAT3, AND ENZYME REGULATION. RX PubMed=16568091; DOI=10.1038/sj.onc.1209501; RA Liu L., Gao Y., Qiu H., Miller W.T., Poli V., Reich N.C.; RT "Identification of STAT3 as a specific substrate of breast tumor RT kinase."; RL Oncogene 25:4904-4912(2006). RN [22] RP ENZYME REGULATION, AND MUTAGENESIS OF TRP-44. RX PubMed=17822667; DOI=10.1016/j.bbrc.2007.08.055; RA Kim H.I.E., Jung J., Lee E.S., Kim Y.C., Lee W., Lee S.T.; RT "Molecular dissection of the interaction between the SH3 domain and RT the SH2-Kinase Linker region in PTK6."; RL Biochem. Biophys. Res. Commun. 362:829-834(2007). RN [23] RP FUNCTION IN PHOSPHORYLATION OF STAT5B. RX PubMed=17997837; DOI=10.1186/bcr1794; RA Weaver A.M., Silva C.M.; RT "Signal transducer and activator of transcription 5b: a new target of RT breast tumor kinase/protein tyrosine kinase 6."; RL Breast Cancer Res. 9:R79-R79(2007). RN [24] RP FUNCTION IN PHOSPHORYLATION OF ARHGAP35. RX PubMed=18829532; DOI=10.1158/0008-5472.CAN-08-0997; RA Shen C.H., Chen H.Y., Lin M.S., Li F.Y., Chang C.C., Kuo M.L., RA Settleman J., Chen R.H.; RT "Breast tumor kinase phosphorylates p190RhoGAP to regulate rho and ras RT and promote breast carcinoma growth, migration, and invasion."; RL Cancer Res. 68:7779-7787(2008). RN [25] RP INTERACTION WITH ADAM15. RX PubMed=18296648; DOI=10.1158/1541-7786.MCR-07-2028; RA Zhong J.L., Poghosyan Z., Pennington C.J., Scott X., Handsley M.M., RA Warn A., Gavrilovic J., Honert K., Kruger A., Span P.N., Sweep F.C., RA Edwards D.R.; RT "Distinct functions of natural ADAM-15 cytoplasmic domain variants in RT human mammary carcinoma."; RL Mol. Cancer Res. 6:383-394(2008). RN [26] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-114, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of RT the kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [27] RP INTERACTION WITH ERBB2. RX PubMed=18719096; DOI=10.1073/pnas.0805009105; RA Xiang B., Chatti K., Qiu H., Lakshmi B., Krasnitz A., Hicks J., Yu M., RA Miller W.T., Muthuswamy S.K.; RT "Brk is coamplified with ErbB2 to promote proliferation in breast RT cancer."; RL Proc. Natl. Acad. Sci. U.S.A. 105:12463-12468(2008). RN [28] RP INTERACTION WITH SFPQ. RX PubMed=19439179; DOI=10.1016/j.cellsig.2009.04.008; RA Lukong K.E., Huot M.E., Richard S.; RT "BRK phosphorylates PSF promoting its cytoplasmic localization and RT cell cycle arrest."; RL Cell. Signal. 21:1415-1422(2009). RN [29] RP REVIEW ON FUNCTION. RX PubMed=20193745; DOI=10.1016/j.bbcan.2010.02.003; RA Brauer P.M., Tyner A.L.; RT "Building a better understanding of the intracellular tyrosine kinase RT PTK6 - BRK by BRK."; RL Biochim. Biophys. Acta 1806:66-73(2010). RN [30] RP PHOSPHORYLATION OF CTNNB1, AND INTERACTION WITH CTNNB1. RX PubMed=20026641; DOI=10.1242/jcs.053264; RA Palka-Hamblin H.L., Gierut J.J., Bie W., Brauer P.M., Zheng Y., RA Asara J.M., Tyner A.L.; RT "Identification of beta-catenin as a target of the intracellular RT tyrosine kinase PTK6."; RL J. Cell Sci. 123:236-245(2010). RN [31] RP FUNCTION (ISOFORM 2), AND INTERACTION (ISOFORM 2) WITH KHDRBS1 AND RP CTNNB1. RX PubMed=21479203; DOI=10.1371/journal.pone.0014789; RA Brauer P.M., Zheng Y., Evans M.D., Dominguez-Brauer C., Peehl D.M., RA Tyner A.L.; RT "The alternative splice variant of protein tyrosine kinase 6 RT negatively regulates growth and enhances PTK6-mediated inhibition of RT beta-catenin."; RL PLoS ONE 6:E14789-E14789(2011). RN [32] RP STRUCTURE BY NMR OF 75-174. RX PubMed=15056653; DOI=10.1074/jbc.M313185200; RA Hong E., Shin J., Kim H.I., Lee S.T., Lee W.; RT "Solution structure and backbone dynamics of the non-receptor protein- RT tyrosine kinase-6 Src homology 2 domain."; RL J. Biol. Chem. 279:29700-29708(2004). RN [33] RP VARIANTS [LARGE SCALE ANALYSIS] PHE-16 AND THR-436. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). 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 CC tumor growth. Function seems to be context dependent and differ CC depending on cell type, as well as its intracellular localization. CC A number of potential nuclear and cytoplasmic substrates have been CC identified. These include the RNA-binding proteins: KHDRBS1/SAM68, CC KHDRBS2/SLM1, KHDRBS3/SLM2 and SFPQ/PSF; transcription factors: CC STAT3 and STAT5A/B and a variety of signaling molecules: CC ARHGAP35/p190RhoGAP, PXN/paxillin, BTK/ATK, STAP2/BKS. Associates CC also with a variety of proteins that are likely upstream of PTK6 CC in various signaling pathways, or for which PTK6 may play an CC adapter-like role. These proteins include ADAM15, EGFR, ERBB2, CC ERBB3 and IRS4. In normal or non-tumorigenic tissues, PTK6 CC promotes cellular differentiation and apoptosis. In tumors PTK6 CC contributes to cancer progression by sensitizing cells to CC mitogenic signals and enhancing proliferation, anchorage- CC 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 CC and PI3 kinase. Contributes to migration and proliferation by CC contributing to EGF-mediated phosphorylation of CC ARHGAP35/p190RhoGAP, which promotes association with CC RASA1/p120RasGAP, inactivating RhoA while activating RAS. EGF CC stimulation resulted in phosphorylation of PNX/Paxillin by PTK6 CC and activation of RAC1 via CRK/CrKII, thereby promoting migration CC and invasion. PTK6 activates STAT3 and STAT5B to promote CC proliferation. Nuclear PTK6 may be important for regulating growth CC in normal epithelia, while cytoplasmic PTK6 might activate CC oncogenic signaling pathways. CC -!- FUNCTION: Isoform 2 inhibits PTK6 phosphorylation and PTK6 CC association with other tyrosine-phosphorylated proteins. CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a CC [protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE- CC ProRule:PRU10028}. CC -!- ENZYME REGULATION: Activated by EGF, NRG1 and IGF1. Inhibited by CC SOCS3 to phosphorylate STAT3. Stabilized in the inactive form by CC an association between the SH3 domain and the SH2-TK linker CC region. Interaction between Trp-184 within SH2-TK linker region CC and the catalytic domain appears essential for positive regulation CC of kinase activity. {ECO:0000269|PubMed:12121988, CC ECO:0000269|PubMed:15870689, ECO:0000269|PubMed:15961400, CC ECO:0000269|PubMed:16568091, ECO:0000269|PubMed:17822667}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=83 uM for ATP {ECO:0000269|PubMed:12121988}; CC Vmax=37 nmol/min/mg enzyme {ECO:0000269|PubMed:12121988}; CC -!- SUBUNIT: Interacts with GAP-A.p65 (By similarity). Interacts (via CC SH3 and SH2 domains) with KHDRBS1. Interacts (via SH3 and SH2 CC domains) with phosphorylated IRS4. Interacts with ADAM15. CC Interacts (via SH3 domain) with SFPQ. Interacts with EGFR and CC ERBB2. Interacts with STAP2. Interacts with PNX. Interacts with CC SFPQ. Interacts with PTK/ATK. Interacts with CTNNB1. {ECO:0000250, CC ECO:0000269|PubMed:10913193, ECO:0000269|PubMed:10980601, CC ECO:0000269|PubMed:15539407, ECO:0000269|PubMed:15572663, CC ECO:0000269|PubMed:15870689, ECO:0000269|PubMed:18296648, CC ECO:0000269|PubMed:18719096, ECO:0000269|PubMed:19439179, CC ECO:0000269|PubMed:20026641, ECO:0000269|PubMed:8940083}. CC -!- INTERACTION: CC Self; NbExp=2; IntAct=EBI-1383632, EBI-1383632; CC P04626:ERBB2; NbExp=2; IntAct=EBI-1383632, EBI-641062; CC Q13480:GAB1; NbExp=6; IntAct=EBI-1383632, EBI-517684; CC P10721:KIT; NbExp=4; IntAct=EBI-1383632, EBI-1379503; CC P23246:SFPQ; NbExp=5; IntAct=EBI-1383632, EBI-355453; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell projection, ruffle. CC Membrane {ECO:0000250}. Note=Colocalizes with KHDRBS1, KHDRBS2 or CC KHDRBS3, within the nucleus. Nuclear localization in epithelial CC cells of normal prostate but cytoplasmic localization in cancer CC prostate. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13882-1; Sequence=Displayed; CC Name=2; Synonyms=ALT-PTK6, deltam5; CC IsoId=Q13882-2; Sequence=VSP_042066, VSP_042067; CC -!- TISSUE SPECIFICITY: Epithelia-specific. Very high level in colon CC and high levels in small intestine and prostate, and low levels in CC some fetal tissues. Not expressed in breast or ovarian tissue but CC expressed in high percentage of breast and ovarian cancers. Also CC overexpressed in some metastatic melanomas, lymphomas, colon CC cancers, squamous cell carcinomas and prostate cancers. Also found CC in melanocytes. Not expressed in heart, brain, placenta, lung, CC liver, skeletal muscle, kidney and pancreas. Isoform 2 is present CC in prostate epithelial cell lines derived from normal prostate and CC prostate adenocarcinomas, as well as in a variety of cell lines. CC {ECO:0000269|PubMed:12833144, ECO:0000269|PubMed:15509496, CC ECO:0000269|PubMed:16651629, ECO:0000269|PubMed:9185712}. CC -!- DOMAIN: The SH3 domain plays a major role in substrate CC interactions. The SH2 domain of PTK6 plays a role in protein- CC protein interactions, but is likely more important for the CC regulation of catalytic activity. CC -!- PTM: Autophosphorylated. Autophosphorylation of Tyr-342 leads to CC an increase of kinase activity. Tyr-447 binds to the SH2 domain CC when phosphorylated and negatively regulates kinase activity. CC {ECO:0000269|PubMed:12121988, ECO:0000269|PubMed:15471878, CC ECO:0000269|PubMed:18691976, ECO:0000269|PubMed:20026641}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein CC kinase family. BRK/PTK6/SIK subfamily. {ECO:0000255|PROSITE- CC ProRule:PRU00159}. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- SIMILARITY: Contains 1 SH2 domain. {ECO:0000255|PROSITE- CC ProRule:PRU00191}. CC -!- SIMILARITY: Contains 1 SH3 domain. {ECO:0000255|PROSITE- CC ProRule:PRU00192}. CC -!- SEQUENCE CAUTION: CC Sequence=BAG62908.1; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X78549; CAA55295.1; -; mRNA. DR EMBL; U61412; AAC34935.1; -; Genomic_DNA. DR EMBL; U61406; AAC34935.1; JOINED; Genomic_DNA. DR EMBL; U61407; AAC34935.1; JOINED; Genomic_DNA. DR EMBL; U61408; AAC34935.1; JOINED; Genomic_DNA. DR EMBL; U61409; AAC34935.1; JOINED; Genomic_DNA. DR EMBL; U61410; AAC34935.1; JOINED; Genomic_DNA. DR EMBL; U61411; AAC34935.1; JOINED; Genomic_DNA. DR EMBL; AK315232; BAG37660.1; -; mRNA. DR EMBL; AK301364; BAG62908.1; ALT_SEQ; mRNA. DR EMBL; AL121829; CAC15525.1; -; Genomic_DNA. DR EMBL; BC035843; AAH35843.1; -; mRNA. DR CCDS; CCDS13524.1; -. [Q13882-1] DR CCDS; CCDS74750.1; -. [Q13882-2] DR PIR; S49016; S49016. DR RefSeq; NP_001243287.1; NM_001256358.1. [Q13882-2] DR RefSeq; NP_005966.1; NM_005975.3. [Q13882-1] DR UniGene; Hs.51133; -. DR PDB; 1RJA; NMR; -; A=75-174. DR PDB; 2KGT; NMR; -; A=1-72. DR PDBsum; 1RJA; -. DR PDBsum; 2KGT; -. DR ProteinModelPortal; Q13882; -. DR SMR; Q13882; 1-450. DR BioGrid; 111720; 13. DR DIP; DIP-39785N; -. DR IntAct; Q13882; 10. DR MINT; MINT-1494499; -. DR STRING; 9606.ENSP00000217185; -. DR BindingDB; Q13882; -. DR ChEMBL; CHEMBL4601; -. DR DrugBank; DB05294; Vandetanib. DR GuidetoPHARMACOLOGY; 2182; -. DR PhosphoSite; Q13882; -. DR DMDM; 8928302; -. DR MaxQB; Q13882; -. DR PaxDb; Q13882; -. DR PRIDE; Q13882; -. DR DNASU; 5753; -. DR Ensembl; ENST00000217185; ENSP00000217185; ENSG00000101213. [Q13882-2] DR Ensembl; ENST00000542869; ENSP00000442460; ENSG00000101213. [Q13882-1] DR GeneID; 5753; -. DR KEGG; hsa:5753; -. DR UCSC; uc002yfg.4; human. [Q13882-1] DR UCSC; uc011aay.3; human. [Q13882-2] DR CTD; 5753; -. DR GeneCards; GC20M062159; -. DR HGNC; HGNC:9617; PTK6. DR HPA; CAB032952; -. DR HPA; HPA036070; -. DR HPA; HPA036071; -. DR MIM; 602004; gene. DR neXtProt; NX_Q13882; -. DR PharmGKB; PA33960; -. DR eggNOG; COG0515; -. DR GeneTree; ENSGT00760000118938; -. DR HOGENOM; HOG000233858; -. DR HOVERGEN; HBG008761; -. DR InParanoid; Q13882; -. DR KO; K08894; -. DR OMA; VRHYKIW; -. DR OrthoDB; EOG73BVCD; -. DR PhylomeDB; Q13882; -. DR TreeFam; TF351634; -. DR BRENDA; 2.7.10.2; 2681. DR SignaLink; Q13882; -. DR EvolutionaryTrace; Q13882; -. DR GeneWiki; PTK6; -. DR GenomeRNAi; 5753; -. DR NextBio; 22386; -. DR PRO; PR:Q13882; -. DR Proteomes; UP000005640; Chromosome 20. DR Bgee; Q13882; -. DR CleanEx; HS_PTK6; -. DR Genevestigator; Q13882; -. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0001726; C:ruffle; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IDA:UniProtKB. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:Ensembl. DR GO; GO:0016477; P:cell migration; IDA:UniProtKB. DR GO; GO:0071300; P:cellular response to retinoic acid; IMP:BHF-UCL. DR GO; GO:0060575; P:intestinal epithelial cell differentiation; IEA:Ensembl. DR GO; GO:0045926; P:negative regulation of growth; IEA:Ensembl. DR GO; GO:0061099; P:negative regulation of protein tyrosine kinase activity; IDA:UniProtKB. DR GO; GO:0010976; P:positive regulation of neuron projection development; IMP:BHF-UCL. DR GO; GO:0046777; P:protein autophosphorylation; IMP:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc. DR GO; GO:0042503; P:tyrosine phosphorylation of Stat3 protein; IDA:UniProtKB. DR GO; GO:0042506; P:tyrosine phosphorylation of Stat5 protein; IDA:UniProtKB. DR Gene3D; 3.30.505.10; -; 1. DR InterPro; IPR011009; Kinase-like_dom. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR000980; SH2. DR InterPro; IPR001452; SH3_domain. DR InterPro; IPR008266; Tyr_kinase_AS. DR InterPro; IPR020635; Tyr_kinase_cat_dom. DR Pfam; PF07714; Pkinase_Tyr; 1. DR Pfam; PF00017; SH2; 1. DR Pfam; PF14604; SH3_9; 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; SSF50044; SSF50044; 1. DR SUPFAM; SSF55550; SSF55550; 1. DR SUPFAM; SSF56112; SSF56112; 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 3D-structure; Alternative splicing; ATP-binding; Cell projection; KW Complete proteome; Cytoplasm; Kinase; Membrane; Nucleotide-binding; KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome; SH2 domain; KW SH3 domain; Transferase; Tyrosine-protein kinase. FT CHAIN 1 451 Protein-tyrosine kinase 6. FT /FTId=PRO_0000088133. FT DOMAIN 11 72 SH3. {ECO:0000255|PROSITE- FT ProRule:PRU00192}. FT DOMAIN 78 170 SH2. {ECO:0000255|PROSITE- FT ProRule:PRU00191}. FT DOMAIN 191 445 Protein kinase. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT NP_BIND 197 205 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT REGION 171 190 Linker. FT ACT_SITE 312 312 Proton acceptor. {ECO:0000255|PROSITE- FT ProRule:PRU00159, ECO:0000255|PROSITE- FT ProRule:PRU10028}. FT BINDING 219 219 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT MOD_RES 13 13 Phosphotyrosine; by autocatalysis. FT MOD_RES 61 61 Phosphotyrosine; by autocatalysis. FT MOD_RES 66 66 Phosphotyrosine; by autocatalysis. FT MOD_RES 114 114 Phosphotyrosine; by autocatalysis. FT {ECO:0000269|PubMed:18691976}. FT MOD_RES 342 342 Phosphotyrosine; by autocatalysis. FT {ECO:0000269|PubMed:12121988}. FT MOD_RES 351 351 Phosphotyrosine; by autocatalysis. FT {ECO:0000269|PubMed:12121988}. FT MOD_RES 447 447 Phosphotyrosine. FT {ECO:0000269|PubMed:12121988}. FT VAR_SEQ 78 134 WFFGCISRSEAVRRLQAEGNATGAFLIRVSEKPSADYVLSV FT RDTQAVRHYKIWRRAG -> AGHAGCAALQDLAACRGPAAP FT ERGGVLPQPARACELPQGPEPVPRPAAGRALPEARA (in FT isoform 2). {ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:9333026}. FT /FTId=VSP_042066. FT VAR_SEQ 135 451 Missing (in isoform 2). FT {ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:9333026}. FT /FTId=VSP_042067. FT VARIANT 16 16 L -> F (in a renal papillary sample; FT somatic mutation). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041760. FT VARIANT 436 436 A -> T (in dbSNP:rs56145017). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041761. FT MUTAGEN 44 44 W->A: Strong decrease in STAP2 FT phosphorylation. Markedly decreased FT interaction between SH3 domain the linker FT region. {ECO:0000269|PubMed:10980601, FT ECO:0000269|PubMed:17822667}. FT MUTAGEN 66 66 Y->A: Decrease in STAP2 phosphorylation. FT {ECO:0000269|PubMed:10980601}. FT MUTAGEN 105 105 R->L: Decrease in STAP2 phosphorylation. FT {ECO:0000269|PubMed:10980601}. FT MUTAGEN 184 184 W->A: Abrogates interaction between PTK6- FT domain kinase and PTK6-linker. Abrogates FT autophosphorylation and phosphorylation FT of KHDRBS1. FT {ECO:0000269|PubMed:15961400}. FT MUTAGEN 219 219 K->M: Abolishes kinase activity and cell FT transformation, and phosphorylation of FT STAP2. {ECO:0000269|PubMed:10980601, FT ECO:0000269|PubMed:15471878, FT ECO:0000269|PubMed:8940083}. FT MUTAGEN 342 342 Y->A: 3-fold lower specific kinase FT activity. Decrease, but still FT significant, autophosphorylation. FT Decrease, but still significant, FT autophosphorylation; when associated to FT A-447. {ECO:0000269|PubMed:12121988}. FT MUTAGEN 447 447 Y->F: Decrease in transforming potential FT and increase in the kinase activity FT level. Decrease, but still significant, FT autophosphorylation; when associated to FT A-342. {ECO:0000269|PubMed:12121988, FT ECO:0000269|PubMed:15471878, FT ECO:0000269|PubMed:8940083}. FT STRAND 12 14 {ECO:0000244|PDB:2KGT}. FT STRAND 35 40 {ECO:0000244|PDB:2KGT}. FT STRAND 45 50 {ECO:0000244|PDB:2KGT}. FT STRAND 56 62 {ECO:0000244|PDB:2KGT}. FT TURN 64 66 {ECO:0000244|PDB:2KGT}. FT STRAND 67 70 {ECO:0000244|PDB:2KGT}. FT HELIX 85 92 {ECO:0000244|PDB:1RJA}. FT STRAND 102 106 {ECO:0000244|PDB:1RJA}. FT STRAND 108 112 {ECO:0000244|PDB:1RJA}. FT STRAND 114 118 {ECO:0000244|PDB:1RJA}. FT STRAND 125 131 {ECO:0000244|PDB:1RJA}. FT STRAND 133 135 {ECO:0000244|PDB:1RJA}. FT STRAND 137 140 {ECO:0000244|PDB:1RJA}. FT STRAND 143 147 {ECO:0000244|PDB:1RJA}. FT HELIX 148 157 {ECO:0000244|PDB:1RJA}. FT STRAND 162 164 {ECO:0000244|PDB:1RJA}. SQ SEQUENCE 451 AA; 51834 MW; CDCAC0EE242E1BD7 CRC64; MVSRDQAHLG PKYVGLWDFK SRTDEELSFR AGDVFHVARK EEQWWWATLL DEAGGAVAQG YVPHNYLAER ETVESEPWFF GCISRSEAVR RLQAEGNATG AFLIRVSEKP SADYVLSVRD TQAVRHYKIW RRAGGRLHLN EAVSFLSLPE LVNYHRAQSL SHGLRLAAPC RKHEPEPLPH WDDWERPREE FTLCRKLGSG YFGEVFEGLW KDRVQVAIKV ISRDNLLHQQ MLQSEIQAMK KLRHKHILAL YAVVSVGDPV YIITELMAKG SLLELLRDSD EKVLPVSELL DIAWQVAEGM CYLESQNYIH RDLAARNILV GENTLCKVGD FGLARLIKED VYLSHDHNIP YKWTAPEALS RGHYSTKSDV WSFGILLHEM FSRGQVPYPG MSNHEAFLRV DAGYRMPCPL ECPPSVHKLM LTCWCRDPEQ RPCFKALRER LSSFTSYENP T //