ACK1_HUMAN
ID ACK1_HUMAN Reviewed; 1038 AA.
AC Q07912; Q6ZMQ0; Q8N6U7; Q96H59;
DT 24-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 05-MAY-2009, sequence version 3.
DT 03-AUG-2022, entry version 223.
DE RecName: Full=Activated CDC42 kinase 1;
DE Short=ACK-1;
DE EC=2.7.10.2 {ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:18993068, ECO:0000269|PubMed:20333297};
DE EC=2.7.11.1 {ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:18993068};
DE AltName: Full=Tyrosine kinase non-receptor protein 2;
GN Name=TNK2; Synonyms=ACK1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND INTERACTION WITH CDC42.
RC TISSUE=Hippocampus;
RX PubMed=8497321; DOI=10.1038/363364a0;
RA Manser E., Leung T., Salihuddin H., Tan L., Lim L.;
RT "A non-receptor tyrosine kinase that inhibits the GTPase activity of
RT p21cdc42.";
RL Nature 363:364-367(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANT LEU-725.
RC TISSUE=Brain;
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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain, and Uterus;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP INTERACTION WITH CSPG4.
RX PubMed=10587647; DOI=10.1038/70302;
RA Eisenmann K.M., McCarthy J.B., Simpson M.A., Keely P.J., Guan J.-L.,
RA Tachibana K., Lim L., Manser E., Furcht L.T., Iida J.;
RT "Melanoma chondroitin sulphate proteoglycan regulates cell spreading
RT through Cdc42, Ack-1 and p130cas.";
RL Nat. Cell Biol. 1:507-513(1999).
RN [6]
RP FUNCTION AS MCF2 KINASE, CATALYTIC ACTIVITY, AND COFACTOR.
RX PubMed=10652228; DOI=10.1006/bbrc.2000.2106;
RA Kato J., Kaziro Y., Satoh T.;
RT "Activation of the guanine nucleotide exchange factor Dbl following ACK1-
RT dependent tyrosine phosphorylation.";
RL Biochem. Biophys. Res. Commun. 268:141-147(2000).
RN [7]
RP FUNCTION.
RX PubMed=11278436; DOI=10.1074/jbc.m008795200;
RA Teo M., Tan L., Lim L., Manser E.;
RT "The tyrosine kinase ACK1 associates with clathrin-coated vesicles through
RT a binding motif shared by arrestin and other adaptors.";
RL J. Biol. Chem. 276:18392-18398(2001).
RN [8]
RP SUBCELLULAR LOCATION.
RX PubMed=14733946; DOI=10.1016/j.bbrc.2003.12.137;
RA Ahmed I., Calle Y., Sayed M.A., Kamal J.M., Rengaswamy P., Manser E.,
RA Meiners S., Nur-E-Kamal A.;
RT "Cdc42-dependent nuclear translocation of non-receptor tyrosine kinase,
RT ACK.";
RL Biochem. Biophys. Res. Commun. 314:571-579(2004).
RN [9]
RP AUTOPHOSPHORYLATION, INTERACTION WITH HSP90AB1; MTERK AND WWOX, AND
RP MUTAGENESIS OF LYS-158 AND LEU-487.
RX PubMed=16288044; DOI=10.1158/0008-5472.can-05-1127;
RA Mahajan N.P., Whang Y.E., Mohler J.L., Earp H.S.;
RT "Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of
RT Ack1 in polyubiquitination of tumor suppressor Wwox.";
RL Cancer Res. 65:10514-10523(2005).
RN [10]
RP INTERACTION WITH SNX9, AND SUBCELLULAR LOCATION.
RX PubMed=16137687; DOI=10.1016/j.febslet.2005.07.093;
RA Yeow-Fong L., Lim L., Manser E.;
RT "SNX9 as an adaptor for linking synaptojanin-1 to the Cdc42 effector
RT ACK1.";
RL FEBS Lett. 579:5040-5048(2005).
RN [11]
RP FUNCTION AS WAS KINASE, INTERACTION WITH WASL, CATALYTIC ACTIVITY, AND
RP COFACTOR.
RX PubMed=16257963; DOI=10.1074/jbc.m506996200;
RA Yokoyama N., Lougheed J., Miller W.T.;
RT "Phosphorylation of WASP by the Cdc42-associated kinase ACK1: dual
RT hydroxyamino acid specificity in a tyrosine kinase.";
RL J. Biol. Chem. 280:42219-42226(2005).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [13]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=16247015; DOI=10.1073/pnas.0508014102;
RA van der Horst E.H., Degenhardt Y.Y., Strelow A., Slavin A., Chinn L.,
RA Orf J., Rong M., Li S., See L.-H., Nguyen K.Q.C., Hoey T., Wesche H.,
RA Powers S.;
RT "Metastatic properties and genomic amplification of the tyrosine kinase
RT gene ACK1.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:15901-15906(2005).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [15]
RP FUNCTION IN CELL MIGRATION, AND INTERACTION WITH BCAR1; CDC42 AND CRK.
RX PubMed=17038317; DOI=10.1074/jbc.m604342200;
RA Modzelewska K., Newman L.P., Desai R., Keely P.J.;
RT "Ack1 mediates Cdc42-dependent cell migration and signaling to p130Cas.";
RL J. Biol. Chem. 281:37527-37535(2006).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, AND PHOSPHORYLATION AT TYR-284.
RX PubMed=16472662; DOI=10.1016/s0076-6879(06)06018-6;
RA Yokoyama N., Miller W.T.;
RT "Purification and enzyme activity of ACK1.";
RL Methods Enzymol. 406:250-260(2006).
RN [17]
RP INTERACTION WITH AR.
RX PubMed=17494760; DOI=10.1073/pnas.0700420104;
RA Mahajan N.P., Liu Y., Majumder S., Warren M.R., Parker C.E., Mohler J.L.,
RA Earp H.S., Whang Y.E.;
RT "Activated Cdc42-associated kinase Ack1 promotes prostate cancer
RT progression via androgen receptor tyrosine phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:8438-8443(2007).
RN [18]
RP INTERACTION WITH NPHP1.
RX PubMed=18477472; DOI=10.1016/j.bbrc.2008.05.016;
RA Eley L., Moochhala S.H., Simms R., Hildebrandt F., Sayer J.A.;
RT "Nephrocystin-1 interacts directly with Ack1 and is expressed in human
RT collecting duct.";
RL Biochem. Biophys. Res. Commun. 371:877-882(2008).
RN [19]
RP FUNCTION.
RX PubMed=18435854; DOI=10.1186/bcr2087;
RA Howlin J., Rosenkvist J., Andersson T.;
RT "TNK2 preserves epidermal growth factor receptor expression on the cell
RT surface and enhances migration and invasion of human breast cancer cells.";
RL Breast Cancer Res. 10:R36-R36(2008).
RN [20]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=18262180; DOI=10.1016/j.yexcr.2007.12.017;
RA Groevdal L.M., Johannessen L.E., Roedland M.S., Madshus I.H., Stang E.;
RT "Dysregulation of Ack1 inhibits down-regulation of the EGF receptor.";
RL Exp. Cell Res. 314:1292-1300(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-881, AND IDENTIFICATION BY
RP 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 the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [23]
RP INTERACTION WITH NEDD4, AND UBIQUITINATION.
RX PubMed=19144635; DOI=10.1074/jbc.m806877200;
RA Chan W., Tian R., Lee Y.-F., Sit S.T., Lim L., Manser E.;
RT "Down-regulation of active ACK1 is mediated by association with the E3
RT ubiquitin ligase Nedd4-2.";
RL J. Biol. Chem. 284:8185-8194(2009).
RN [24]
RP FUNCTION, AND INTERACTION WITH AXL; LTK; PDGFRL AND GRB2.
RX PubMed=19815557; DOI=10.1074/jbc.m109.072660;
RA Pao-Chun L., Chan P.M., Chan W., Manser E.;
RT "Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is
RT mediated by Grb2: an analysis of ACK1 effects on Axl signaling.";
RL J. Biol. Chem. 284:34954-34963(2009).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-284 AND SER-724, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [26]
RP SUBUNIT, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYR-284, AND DOMAIN
RP SAM-LIKE.
RX PubMed=20979614; DOI=10.1186/1471-2091-11-42;
RA Prieto-Echaguee V., Gucwa A., Brown D.A., Miller W.T.;
RT "Regulation of Ack1 localization and activity by the amino-terminal SAM
RT domain.";
RL BMC Biochem. 11:42-42(2010).
RN [27]
RP FUNCTION, SUBCELLULAR LOCATION, VARIANTS LEU-34; GLN-99; LYS-346 AND
RP ILE-409, CHARACTERIZATION OF VARIANTS LEU-34; GLN-99; LYS-346 AND ILE-409,
RP AND MUTAGENESIS OF LEU-120; LEU-197 AND VAL-365.
RX PubMed=20110370; DOI=10.1074/jbc.m109.060459;
RA Prieto-Echaguee V., Gucwa A., Craddock B.P., Brown D.A., Miller W.T.;
RT "Cancer-associated mutations activate the nonreceptor tyrosine kinase
RT Ack1.";
RL J. Biol. Chem. 285:10605-10615(2010).
RN [28]
RP FUNCTION AS AR KINASE, AND ACTIVITY REGULATION.
RX PubMed=20383201; DOI=10.1038/onc.2010.103;
RA Liu Y., Karaca M., Zhang Z., Gioeli D., Earp H.S., Whang Y.E.;
RT "Dasatinib inhibits site-specific tyrosine phosphorylation of androgen
RT receptor by Ack1 and Src kinases.";
RL Oncogene 29:3208-3216(2010).
RN [29]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, INTERACTION WITH AKT1, SUBCELLULAR
RP LOCATION, CHARACTERIZATION OF VARIANT LYS-346, PHOSPHORYLATION AT TYR-284,
RP AND TISSUE SPECIFICITY.
RX PubMed=20333297; DOI=10.1371/journal.pone.0009646;
RA Mahajan K., Coppola D., Challa S., Fang B., Chen Y.A., Zhu W., Lopez A.S.,
RA Koomen J., Engelman R.W., Rivera C., Muraoka-Cook R.S., Cheng J.Q.,
RA Schoenbrunn E., Sebti S.M., Earp H.S., Mahajan N.P.;
RT "Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its
RT activation.";
RL PLoS ONE 5:E9646-E9646(2010).
RN [30]
RP PHOSPHORYLATION AT TYR-284, TISSUE SPECIFICITY, AND ACTIVITY REGULATION.
RX PubMed=20623637; DOI=10.1002/pros.21163;
RA Mahajan K., Challa S., Coppola D., Lawrence H., Luo Y., Gevariya H.,
RA Zhu W., Chen Y.A., Lawrence N.J., Mahajan N.P.;
RT "Effect of Ack1 tyrosine kinase inhibitor on ligand-independent androgen
RT receptor activity.";
RL Prostate 70:1274-1285(2010).
RN [31]
RP PHOSPHORYLATION AT TYR-284, AND INTERACTION WITH SRC.
RX PubMed=21309750; DOI=10.1042/bj20102156;
RA Chan W., Sit S.T., Manser E.;
RT "The Cdc42-associated kinase ACK1 is not auto-inhibited but requires Src
RT for activation.";
RL Biochem. J. 435:355-364(2011).
RN [32]
RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT TYR-284; TYR-518; TYR-827;
RP TYR-859 AND TYR-872.
RX PubMed=21169560; DOI=10.1091/mbc.e10-07-0637;
RA Shen H., Ferguson S.M., Dephoure N., Park R., Yang Y., Volpicelli-Daley L.,
RA Gygi S., Schlessinger J., De Camilli P.;
RT "Constitutive activated Cdc42-associated kinase (Ack) phosphorylation at
RT arrested endocytic clathrin-coated pits of cells that lack dynamin.";
RL Mol. Biol. Cell 22:493-502(2011).
RN [33]
RP REVIEW ON TUMOR GROWTH.
RX PubMed=20432460; DOI=10.1002/jcp.22162;
RA Mahajan K., Mahajan N.P.;
RT "Shepherding AKT and androgen receptor by Ack1 tyrosine kinase.";
RL J. Cell. Physiol. 224:327-333(2010).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [35]
RP STRUCTURE BY NMR OF 448-489.
RX PubMed=10360579; DOI=10.1038/20732;
RA Mott H.R., Owen D., Nietlispach D., Lowe P.N., Manser E., Lim L.,
RA Laue E.D.;
RT "Structure of the small G protein Cdc42 bound to the GTPase-binding domain
RT of ACK.";
RL Nature 399:384-388(1999).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 107-395, AND PHOSPHORYLATION AT
RP TYR-284.
RX PubMed=15308621; DOI=10.1074/jbc.m406703200;
RA Lougheed J.C., Chen R.-H., Mak P., Stout T.J.;
RT "Crystal structures of the phosphorylated and unphosphorylated kinase
RT domains of the Cdc42-associated tyrosine kinase ACK1.";
RL J. Biol. Chem. 279:44039-44045(2004).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 117-392 IN COMPLEX WITH INHIBITOR,
RP AND CATALYTIC ACTIVITY.
RX PubMed=18993068; DOI=10.1016/j.bmcl.2008.10.092;
RA Kopecky D.J., Hao X., Chen Y., Fu J., Jiao X., Jaen J.C., Cardozo M.G.,
RA Liu J., Wang Z., Walker N.P., Wesche H., Li S., Farrelly E., Xiao S.H.,
RA Kayser F.;
RT "Identification and optimization of N3,N6-diaryl-1H-pyrazolo[3,4-
RT d]pyrimidine-3,6-diamines as a novel class of ACK1 inhibitors.";
RL Bioorg. Med. Chem. Lett. 18:6352-6356(2008).
RN [38]
RP VARIANTS LEU-34; ARG-71; GLN-99; TRP-99; MET-152; LYS-346; ILE-409;
RP SER-507; LEU-725; GLN-748 AND HIS-1038.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [39]
RP VARIANT MET-638, INTERACTION WITH NEDD4 AND NEDD4L, AND CHARACTERIZATION OF
RP VARIANT MET-638.
RX PubMed=23686771; DOI=10.1002/ana.23934;
RA Hitomi Y., Heinzen E.L., Donatello S., Dahl H.H., Damiano J.A.,
RA McMahon J.M., Berkovic S.F., Scheffer I.E., Legros B., Rai M.,
RA Weckhuysen S., Suls A., De Jonghe P., Pandolfo M., Goldstein D.B.,
RA Van Bogaert P., Depondt C.;
RT "Mutations in TNK2 in severe autosomal recessive infantile onset
RT epilepsy.";
RL Ann. Neurol. 74:496-501(2013).
CC -!- FUNCTION: Non-receptor tyrosine-protein and serine/threonine-protein
CC kinase that is implicated in cell spreading and migration, cell
CC survival, cell growth and proliferation. Transduces extracellular
CC signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR,
CC MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated
CC endocytosis through binding to epidermal growth factor receptor (EGFR)
CC and clathrin. Binds to both poly- and mono-ubiquitin and regulates
CC ligand-induced degradation of EGFR, thereby contributing to the
CC accumulation of EGFR at the limiting membrane of early endosomes.
CC Downstream effector of CDC42 which mediates CDC42-dependent cell
CC migration via phosphorylation of BCAR1. May be involved both in adult
CC synaptic function and plasticity and in brain development. Activates
CC AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267'
CC and 'Tyr-363' thereby promoting its recruitment to androgen-responsive
CC enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates
CC MCF2, thereby enhancing its activity as a guanine nucleotide exchange
CC factor (GEF) toward Rho family proteins. Contributes to the control of
CC AXL receptor levels. Confers metastatic properties on cancer cells and
CC promotes tumor growth by negatively regulating tumor suppressor such as
CC WWOX and positively regulating pro-survival factors such as AKT1 and
CC AR. Phosphorylates WASP (PubMed:20110370).
CC {ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:11278436,
CC ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:16257963,
CC ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:17038317,
CC ECO:0000269|PubMed:18262180, ECO:0000269|PubMed:18435854,
CC ECO:0000269|PubMed:19815557, ECO:0000269|PubMed:20110370,
CC ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20383201}.
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 ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:16257963,
CC ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:18993068,
CC ECO:0000269|PubMed:20333297};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:18993068};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000269|PubMed:16257963,
CC ECO:0000269|PubMed:18993068};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:16257963,
CC ECO:0000269|PubMed:20333297};
CC -!- ACTIVITY REGULATION: Inhibited by AIM-100 (4-amino-5,6-biaryl-furo[2,3-
CC d]pyrimidine), which suppresses activating phosphorylation at Tyr-284.
CC Repressed by dasatinib. {ECO:0000269|PubMed:20383201,
CC ECO:0000269|PubMed:20623637}.
CC -!- SUBUNIT: Interacts with NEDD4 (via WW3 domain). NEDD4L and EGF promote
CC association with NEDD4 (By similarity). Homodimer. Interacts with AR,
CC CDC42, WWASL and WWOX. Interacts with CSPG4 (activated). Interacts with
CC MERTK (activated); stimulates autophosphorylation. May interact
CC (phosphorylated) with HSP90AB1; maintains kinase activity. Interacts
CC with NPHP1. Interacts with SNX9 (via SH3 domain). Interacts with SRC
CC (via SH2 and SH3 domain). Interacts with EGFR, and this interaction is
CC dependent on EGF stimulation and kinase activity of EGFR. Interacts
CC (via kinase domain) with AKT1. Part of a collagen stimulated complex
CC involved in cell migration composed of CDC42, CRK, TNK2 and
CC BCAR1/p130cas. Interacts with BCAR1/p130cas via SH3 domains. Forms
CC complexes with GRB2 and numerous receptor tyrosine kinases (RTK)
CC including LTK, AXL or PDGFRL, in which GRB2 promotes RTK recruitment by
CC TNK2. {ECO:0000250, ECO:0000269|PubMed:10587647,
CC ECO:0000269|PubMed:16137687, ECO:0000269|PubMed:16257963,
CC ECO:0000269|PubMed:16288044, ECO:0000269|PubMed:17038317,
CC ECO:0000269|PubMed:17494760, ECO:0000269|PubMed:18477472,
CC ECO:0000269|PubMed:18993068, ECO:0000269|PubMed:19144635,
CC ECO:0000269|PubMed:19815557, ECO:0000269|PubMed:20333297,
CC ECO:0000269|PubMed:20979614, ECO:0000269|PubMed:21309750,
CC ECO:0000269|PubMed:23686771, ECO:0000269|PubMed:8497321}.
CC -!- INTERACTION:
CC Q07912; P29972: AQP1; NbExp=3; IntAct=EBI-603457, EBI-745213;
CC Q07912; P56945: BCAR1; NbExp=5; IntAct=EBI-603457, EBI-702093;
CC Q07912; P60953-2: CDC42; NbExp=2; IntAct=EBI-603457, EBI-287394;
CC Q07912; Q00610: CLTC; NbExp=3; IntAct=EBI-603457, EBI-354967;
CC Q07912; P07902: GALT; NbExp=3; IntAct=EBI-603457, EBI-750827;
CC Q07912; P08238: HSP90AB1; NbExp=3; IntAct=EBI-603457, EBI-352572;
CC Q07912; Q9HC98: NEK6; NbExp=3; IntAct=EBI-603457, EBI-740364;
CC Q07912; Q7Z3S9: NOTCH2NLA; NbExp=3; IntAct=EBI-603457, EBI-945833;
CC Q07912; O60880: SH2D1A; NbExp=3; IntAct=EBI-603457, EBI-6983382;
CC Q07912; Q07912: TNK2; NbExp=2; IntAct=EBI-603457, EBI-603457;
CC Q07912-2; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-11994780, EBI-3867333;
CC Q07912-2; Q9BQC3: DPH2; NbExp=3; IntAct=EBI-11994780, EBI-10237931;
CC Q07912-2; P07902: GALT; NbExp=3; IntAct=EBI-11994780, EBI-750827;
CC Q07912-2; Q92569: PIK3R3; NbExp=3; IntAct=EBI-11994780, EBI-79893;
CC Q07912-2; O60880: SH2D1A; NbExp=3; IntAct=EBI-11994780, EBI-6983382;
CC Q07912-2; O14796: SH2D1B; NbExp=3; IntAct=EBI-11994780, EBI-3923013;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20333297,
CC ECO:0000269|PubMed:20979614}. Nucleus {ECO:0000269|PubMed:14733946,
CC ECO:0000269|PubMed:20333297}. Endosome {ECO:0000250|UniProtKB:O54967}.
CC Cell junction, adherens junction {ECO:0000305}. Cytoplasmic vesicle
CC membrane; Peripheral membrane protein; Cytoplasmic side
CC {ECO:0000269|PubMed:16137687}. Cytoplasmic vesicle, clathrin-coated
CC vesicle {ECO:0000269|PubMed:16137687, ECO:0000269|PubMed:18262180}.
CC Membrane, clathrin-coated pit {ECO:0000269|PubMed:21169560}. Cytoplasm,
CC perinuclear region {ECO:0000269|PubMed:20110370}. Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:O54967}. Note=The Tyr-284 phosphorylated form is
CC found both in the membrane and nucleus (By similarity). Co-localizes
CC with EGFR on endosomes (PubMed:20333297). Nuclear translocation is
CC CDC42-dependent (By similarity). Detected in long filamentous cytosolic
CC structures where it co-localizes with CTPS1 (By similarity).
CC {ECO:0000250|UniProtKB:O54967, ECO:0000269|PubMed:20333297}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q07912-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q07912-2; Sequence=VSP_008655, VSP_008656;
CC Name=3;
CC IsoId=Q07912-3; Sequence=VSP_037284, VSP_037285, VSP_037286;
CC -!- TISSUE SPECIFICITY: The Tyr-284 phosphorylated form shows a significant
CC increase in expression in breast cancers during the progressive stages
CC i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS),
CC invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM)
CC stages. It also shows a significant increase in expression in prostate
CC cancers during the progressive stages. {ECO:0000269|PubMed:16247015,
CC ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20623637}.
CC -!- DOMAIN: The EBD (EGFR-binding domain) domain is necessary for
CC interaction with EGFR. {ECO:0000250}.
CC -!- DOMAIN: The SAM-like domain is necessary for NEDD4-mediated
CC ubiquitination. Promotes membrane localization and dimerization to
CC allow for autophosphorylation. {ECO:0000269|PubMed:20979614}.
CC -!- DOMAIN: The UBA domain binds both poly- and mono-ubiquitin.
CC {ECO:0000269|PubMed:20979614}.
CC -!- PTM: Autophosphorylation regulates kinase activity. Phosphorylation on
CC Tyr-518 is required for interaction with SRC and is observed during
CC association with clathrin-coated pits. {ECO:0000269|PubMed:15308621,
CC ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:20333297,
CC ECO:0000269|PubMed:20623637, ECO:0000269|PubMed:20979614,
CC ECO:0000269|PubMed:21169560, ECO:0000269|PubMed:21309750}.
CC -!- PTM: Polyubiquitinated by NEDD4 and NEDD4L. Degradation can be induced
CC by EGF and is lysosome-dependent (By similarity). {ECO:0000250}.
CC -!- MISCELLANEOUS: [Isoform 2]: May be produced at very low levels due to a
CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC decay. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH08884.1; Type=Miscellaneous discrepancy; Note=Unlikely isoform. Aberrant splice sites.; Evidence={ECO:0000305};
CC Sequence=BAD18675.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; L13738; AAA53570.2; -; mRNA.
DR EMBL; AK131539; BAD18675.1; ALT_INIT; mRNA.
DR EMBL; AC124944; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC008884; AAH08884.1; ALT_SEQ; mRNA.
DR EMBL; BC028164; AAH28164.1; -; mRNA.
DR CCDS; CCDS33927.1; -. [Q07912-3]
DR CCDS; CCDS33928.1; -. [Q07912-1]
DR PIR; S33596; S33596.
DR RefSeq; NP_001010938.1; NM_001010938.1. [Q07912-3]
DR RefSeq; NP_001294975.1; NM_001308046.1.
DR RefSeq; NP_005772.3; NM_005781.4. [Q07912-1]
DR PDB; 1CF4; NMR; -; B=448-489.
DR PDB; 1U46; X-ray; 2.00 A; A/B=109-395.
DR PDB; 1U4D; X-ray; 2.10 A; A/B=109-395.
DR PDB; 1U54; X-ray; 2.80 A; A/B=109-395.
DR PDB; 3EQP; X-ray; 2.30 A; A/B=117-392.
DR PDB; 3EQR; X-ray; 2.00 A; A/B=117-392.
DR PDB; 4EWH; X-ray; 2.50 A; A/B=117-391.
DR PDB; 4HZR; X-ray; 1.31 A; A/B=115-389.
DR PDB; 4HZS; X-ray; 3.23 A; A/B/C/D=115-453.
DR PDB; 4ID7; X-ray; 3.00 A; A=117-389.
DR PDB; 5ZXB; X-ray; 2.20 A; A/B=117-391.
DR PDB; 6VQM; X-ray; 2.87 A; A/B=109-395.
DR PDB; 7KP6; X-ray; 1.79 A; A/B=110-391.
DR PDBsum; 1CF4; -.
DR PDBsum; 1U46; -.
DR PDBsum; 1U4D; -.
DR PDBsum; 1U54; -.
DR PDBsum; 3EQP; -.
DR PDBsum; 3EQR; -.
DR PDBsum; 4EWH; -.
DR PDBsum; 4HZR; -.
DR PDBsum; 4HZS; -.
DR PDBsum; 4ID7; -.
DR PDBsum; 5ZXB; -.
DR PDBsum; 6VQM; -.
DR PDBsum; 7KP6; -.
DR AlphaFoldDB; Q07912; -.
DR SMR; Q07912; -.
DR BioGRID; 115485; 114.
DR CORUM; Q07912; -.
DR DIP; DIP-33858N; -.
DR IntAct; Q07912; 71.
DR MINT; Q07912; -.
DR STRING; 9606.ENSP00000371341; -.
DR BindingDB; Q07912; -.
DR ChEMBL; CHEMBL4599; -.
DR DrugBank; DB00171; ATP.
DR DrugBank; DB04367; Debromohymenialdisine.
DR DrugBank; DB11986; Entrectinib.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q07912; -.
DR GuidetoPHARMACOLOGY; 2246; -.
DR GlyGen; Q07912; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; Q07912; -.
DR PhosphoSitePlus; Q07912; -.
DR BioMuta; TNK2; -.
DR DMDM; 229462980; -.
DR CPTAC; CPTAC-1779; -.
DR CPTAC; CPTAC-2789; -.
DR EPD; Q07912; -.
DR jPOST; Q07912; -.
DR MassIVE; Q07912; -.
DR MaxQB; Q07912; -.
DR PaxDb; Q07912; -.
DR PeptideAtlas; Q07912; -.
DR PRIDE; Q07912; -.
DR ProteomicsDB; 58556; -. [Q07912-1]
DR ProteomicsDB; 58557; -. [Q07912-2]
DR ProteomicsDB; 58558; -. [Q07912-3]
DR Antibodypedia; 4095; 781 antibodies from 40 providers.
DR CPTC; Q07912; 5 antibodies.
DR DNASU; 10188; -.
DR Ensembl; ENST00000333602.14; ENSP00000329425.6; ENSG00000061938.21. [Q07912-1]
DR Ensembl; ENST00000439230.6; ENSP00000395588.1; ENSG00000061938.21. [Q07912-2]
DR Ensembl; ENST00000671753.1; ENSP00000499858.1; ENSG00000061938.21. [Q07912-3]
DR GeneID; 10188; -.
DR KEGG; hsa:10188; -.
DR UCSC; uc003fvt.2; human. [Q07912-1]
DR CTD; 10188; -.
DR DisGeNET; 10188; -.
DR GeneCards; TNK2; -.
DR HGNC; HGNC:19297; TNK2.
DR HPA; ENSG00000061938; Tissue enhanced (brain).
DR MalaCards; TNK2; -.
DR MIM; 606994; gene.
DR neXtProt; NX_Q07912; -.
DR OpenTargets; ENSG00000061938; -.
DR Orphanet; 391316; Infantile-onset mesial temporal lobe epilepsy with severe cognitive regression.
DR PharmGKB; PA134909759; -.
DR VEuPathDB; HostDB:ENSG00000061938; -.
DR eggNOG; KOG0199; Eukaryota.
DR GeneTree; ENSGT00940000160853; -.
DR HOGENOM; CLU_000288_7_39_1; -.
DR InParanoid; Q07912; -.
DR OrthoDB; 1008736at2759; -.
DR PhylomeDB; Q07912; -.
DR TreeFam; TF316643; -.
DR BRENDA; 2.7.10.2; 2681.
DR PathwayCommons; Q07912; -.
DR SignaLink; Q07912; -.
DR SIGNOR; Q07912; -.
DR BioGRID-ORCS; 10188; 10 hits in 1111 CRISPR screens.
DR ChiTaRS; TNK2; human.
DR EvolutionaryTrace; Q07912; -.
DR GeneWiki; TNK2; -.
DR GenomeRNAi; 10188; -.
DR Pharos; Q07912; Tclin.
DR PRO; PR:Q07912; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q07912; protein.
DR Bgee; ENSG00000061938; Expressed in right hemisphere of cerebellum and 190 other tissues.
DR ExpressionAtlas; Q07912; baseline and differential.
DR Genevisible; Q07912; HS.
DR GO; GO:0005912; C:adherens junction; IEA:UniProtKB-SubCell.
DR GO; GO:0005905; C:clathrin-coated pit; IDA:UniProtKB.
DR GO; GO:0030136; C:clathrin-coated vesicle; IDA:UniProtKB.
DR GO; GO:0097268; C:cytoophidium; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005768; C:endosome; ISS:UniProtKB.
DR GO; GO:0031234; C:extrinsic component of cytoplasmic side of plasma membrane; IBA:GO_Central.
DR GO; GO:0070436; C:Grb2-EGFR complex; IDA:BHF-UCL.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005154; F:epidermal growth factor receptor binding; IDA:BHF-UCL.
DR GO; GO:0005095; F:GTPase inhibitor activity; TAS:ProtInc.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; IDA:UniProtKB.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:UniProtKB.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0050699; F:WW domain binding; ISS:BHF-UCL.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:UniProtKB.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:0016310; P:phosphorylation; IDA:UniProtKB.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:2000369; P:regulation of clathrin-dependent endocytosis; IDA:UniProtKB.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; TAS:ProtInc.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR DisProt; DP01772; -.
DR Gene3D; 4.10.680.10; -; 1.
DR IDEAL; IID00276; -.
DR InterPro; IPR030220; Ack1.
DR InterPro; IPR015116; Cdc42-bd-like.
DR InterPro; IPR037085; Cdc42-bd-like_dom_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR021619; Mig-6.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
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; PTHR14254:SF6; PTHR14254:SF6; 1.
DR Pfam; PF09027; GTPase_binding; 1.
DR Pfam; PF11555; Inhibitor_Mig-6; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF14604; SH3_9; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00326; SH3; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF50044; SSF50044; 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; PS50002; SH3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell junction;
KW Cell membrane; Coated pit; Cytoplasm; Cytoplasmic vesicle; Endocytosis;
KW Endosome; Kinase; Magnesium; Membrane; Metal-binding; Methylation;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; SH3 domain; Transferase;
KW Tyrosine-protein kinase; Ubl conjugation.
FT CHAIN 1..1038
FT /note="Activated CDC42 kinase 1"
FT /id="PRO_0000088058"
FT DOMAIN 126..385
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 388..448
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 454..466
FT /note="CRIB"
FT DOMAIN 958..996
FT /note="UBA"
FT REGION 1..110
FT /note="SAM-like domain"
FT REGION 90..114
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 497..535
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 623..652
FT /note="Required for interaction with SRC"
FT /evidence="ECO:0000269|PubMed:21309750"
FT REGION 632..635
FT /note="Required for interaction with NEDD4"
FT /evidence="ECO:0000250"
FT REGION 659..702
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 718..840
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 733..876
FT /note="EBD domain"
FT /evidence="ECO:0000250"
FT REGION 917..957
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 724..756
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 772..805
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 806..827
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 252
FT /note="Proton acceptor"
FT BINDING 132..140
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT BINDING 158
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 284
FT /note="Phosphotyrosine; by SRC and autocatalysis"
FT /evidence="ECO:0000269|PubMed:15308621,
FT ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:20333297,
FT ECO:0000269|PubMed:20623637, ECO:0000269|PubMed:20979614,
FT ECO:0000269|PubMed:21169560, ECO:0000269|PubMed:21309750,
FT ECO:0007744|PubMed:19369195"
FT MOD_RES 518
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:21169560"
FT MOD_RES 724
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 827
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:21169560"
FT MOD_RES 839
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:O54967"
FT MOD_RES 859
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:21169560"
FT MOD_RES 872
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:21169560"
FT MOD_RES 881
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT VAR_SEQ 1
FT /note="M -> MGERSAYQRLAGGEEGPQRLGGGRM (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_037284"
FT VAR_SEQ 485..528
FT /note="LYLGNPMDPPDLLSVELSTSRPPQHLGGVKKPTYDPVSEDQDPL -> CPFS
FT AFSPGHPPAETCGQVLWTGRREACASDPRLHPVSSRTKGL (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_008655"
FT VAR_SEQ 514
FT /note="K -> KREPPPRPPQPAFFTQ (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_037285"
FT VAR_SEQ 529..1038
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_008656"
FT VAR_SEQ 965..994
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_037286"
FT VARIANT 34
FT /note="R -> L (in a lung adenocarcinoma sample; somatic
FT mutation; increased autophosphorylation at Y-284; increased
FT function in phosphorylation of peptide substrates; no
FT effect on subcellular localization to perinuclear region)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:20110370"
FT /id="VAR_032792"
FT VARIANT 71
FT /note="K -> R (in dbSNP:rs56036945)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_032793"
FT VARIANT 99
FT /note="R -> Q (in an ovarian mucinous carcinoma sample;
FT somatic mutation; increased autophosphorylation at Y-284;
FT increased function in phosphorylation of peptide substrates
FT and WASP; no effect on subcellular localization to
FT perinuclear region; dbSNP:rs113498671)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:20110370"
FT /id="VAR_032794"
FT VARIANT 99
FT /note="R -> W (in dbSNP:rs3747673)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_032795"
FT VARIANT 152
FT /note="T -> M (in dbSNP:rs56161912)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_032796"
FT VARIANT 346
FT /note="E -> K (in an ovarian endometrioid cancer sample;
FT somatic mutation; undergoes autoactivation and causes
FT phosphorylation on Y-284 leading to activation of AKT1;
FT increased autophosphorylation at Y-284; increased function
FT in phosphorylation of peptide substrates and WASP; no
FT effect on catalytic activity itself as the purified kinase
FT domain has activity in vitro comparable to wild-type
FT protein; no effect on subcellular localization to
FT perinuclear region; dbSNP:rs970946035)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:20110370, ECO:0000269|PubMed:20333297"
FT /id="VAR_032797"
FT VARIANT 409
FT /note="M -> I (in a gastric adenocarcinoma sample; somatic
FT mutation; increased autophosphorylation at Y-284; increased
FT function in phosphorylation of peptide substrates and WASP;
FT no effect on subcellular localization to perinuclear
FT region)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:20110370"
FT /id="VAR_032798"
FT VARIANT 507
FT /note="P -> S (in dbSNP:rs35759128)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_032799"
FT VARIANT 638
FT /note="V -> M (found in patients with childhood-onset
FT epilepsy; unknown pathological significance; loss of
FT interaction with NEDD4 and NEDD4L; increased protein
FT abundance; dbSNP:rs201407161)"
FT /evidence="ECO:0000269|PubMed:23686771"
FT /id="VAR_076966"
FT VARIANT 725
FT /note="P -> L (in dbSNP:rs56260729)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:17344846"
FT /id="VAR_032800"
FT VARIANT 748
FT /note="R -> Q (in dbSNP:rs57872314)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_032801"
FT VARIANT 802
FT /note="P -> L (in dbSNP:rs3749333)"
FT /id="VAR_057115"
FT VARIANT 1038
FT /note="R -> H (in dbSNP:rs13433937)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_032802"
FT MUTAGEN 120
FT /note="L->Q: No effect on autophosphorylation at Y-284."
FT /evidence="ECO:0000269|PubMed:20110370"
FT MUTAGEN 158
FT /note="K->R: Loss of autophosphorylation at Y-284."
FT /evidence="ECO:0000269|PubMed:16288044,
FT ECO:0000269|PubMed:20110370"
FT MUTAGEN 197
FT /note="L->Q: No effect on autophosphorylation at Y-284."
FT /evidence="ECO:0000269|PubMed:20110370"
FT MUTAGEN 365
FT /note="V->R: Increased autophosphorylation at Y-284."
FT /evidence="ECO:0000269|PubMed:20110370"
FT MUTAGEN 487
FT /note="L->F: Constantly active kinase."
FT /evidence="ECO:0000269|PubMed:16288044"
FT CONFLICT 138
FT /note="G -> V (in Ref. 4; AAH08884)"
FT /evidence="ECO:0000305"
FT CONFLICT 304..352
FT /note="TRTFSHASDTWMFGVTLWEMFTYGQEPWIGLNGSQILHKIDKEGERLPR ->
FT PPWRDISASSSTQFPHAVPCFPTSLLAKLLLRHSVPASSREIKLVSILC (in Ref.
FT 4; AAH08884)"
FT /evidence="ECO:0000305"
FT CONFLICT 353..1038
FT /note="Missing (in Ref. 4; AAH08884)"
FT /evidence="ECO:0000305"
FT CONFLICT 586
FT /note="A -> P (in Ref. 1; AAA53570)"
FT /evidence="ECO:0000305"
FT CONFLICT 722
FT /note="Missing (in Ref. 1; AAA53570)"
FT /evidence="ECO:0000305"
FT CONFLICT 838..840
FT /note="PRA -> AG (in Ref. 1; AAA53570)"
FT /evidence="ECO:0000305"
FT STRAND 118..120
FT /evidence="ECO:0007829|PDB:4HZS"
FT HELIX 123..125
FT /evidence="ECO:0007829|PDB:4HZR"
FT STRAND 126..133
FT /evidence="ECO:0007829|PDB:4HZR"
FT STRAND 140..146
FT /evidence="ECO:0007829|PDB:4HZR"
FT STRAND 148..150
FT /evidence="ECO:0007829|PDB:3EQP"
FT STRAND 152..159
FT /evidence="ECO:0007829|PDB:4HZR"
FT TURN 164..166
FT /evidence="ECO:0007829|PDB:3EQR"
FT HELIX 171..181
FT /evidence="ECO:0007829|PDB:4HZR"
FT STRAND 192..196
FT /evidence="ECO:0007829|PDB:4HZR"
FT STRAND 198..200
FT /evidence="ECO:0007829|PDB:4HZR"
FT STRAND 202..206
FT /evidence="ECO:0007829|PDB:4HZR"
FT HELIX 213..219
FT /evidence="ECO:0007829|PDB:4HZR"
FT HELIX 221..223
FT /evidence="ECO:0007829|PDB:4HZR"
FT HELIX 226..245
FT /evidence="ECO:0007829|PDB:4HZR"
FT HELIX 255..257
FT /evidence="ECO:0007829|PDB:4HZR"
FT STRAND 258..262
FT /evidence="ECO:0007829|PDB:4HZR"
FT STRAND 265..268
FT /evidence="ECO:0007829|PDB:4HZR"
FT HELIX 273..276
FT /evidence="ECO:0007829|PDB:4HZS"
FT STRAND 283..285
FT /evidence="ECO:0007829|PDB:1U46"
FT HELIX 288..290
FT /evidence="ECO:0007829|PDB:3EQP"
FT HELIX 294..296
FT /evidence="ECO:0007829|PDB:4HZR"
FT HELIX 299..304
FT /evidence="ECO:0007829|PDB:4HZR"
FT STRAND 306..308
FT /evidence="ECO:0007829|PDB:1U46"
FT HELIX 309..324
FT /evidence="ECO:0007829|PDB:4HZR"
FT TURN 325..327
FT /evidence="ECO:0007829|PDB:4HZS"
FT TURN 330..333
FT /evidence="ECO:0007829|PDB:4HZR"
FT HELIX 336..344
FT /evidence="ECO:0007829|PDB:4HZR"
FT HELIX 358..367
FT /evidence="ECO:0007829|PDB:4HZR"
FT HELIX 372..374
FT /evidence="ECO:0007829|PDB:4HZR"
FT HELIX 378..387
FT /evidence="ECO:0007829|PDB:4HZR"
FT STRAND 392..394
FT /evidence="ECO:0007829|PDB:4HZS"
FT STRAND 402..404
FT /evidence="ECO:0007829|PDB:4HZS"
FT STRAND 412..417
FT /evidence="ECO:0007829|PDB:4HZS"
FT STRAND 419..421
FT /evidence="ECO:0007829|PDB:4HZS"
FT STRAND 423..432
FT /evidence="ECO:0007829|PDB:4HZS"
FT STRAND 435..439
FT /evidence="ECO:0007829|PDB:4HZS"
FT HELIX 440..443
FT /evidence="ECO:0007829|PDB:4HZS"
FT STRAND 449..451
FT /evidence="ECO:0007829|PDB:1CF4"
FT TURN 484..486
FT /evidence="ECO:0007829|PDB:1CF4"
SQ SEQUENCE 1038 AA; 114569 MW; 74A1980665BC3E6B CRC64;
MQPEEGTGWL LELLSEVQLQ QYFLRLRDDL NVTRLSHFEY VKNEDLEKIG MGRPGQRRLW
EAVKRRKALC KRKSWMSKVF SGKRLEAEFP PHHSQSTFRK TSPAPGGPAG EGPLQSLTCL
IGEKDLRLLE KLGDGSFGVV RRGEWDAPSG KTVSVAVKCL KPDVLSQPEA MDDFIREVNA
MHSLDHRNLI RLYGVVLTPP MKMVTELAPL GSLLDRLRKH QGHFLLGTLS RYAVQVAEGM
GYLESKRFIH RDLAARNLLL ATRDLVKIGD FGLMRALPQN DDHYVMQEHR KVPFAWCAPE
SLKTRTFSHA SDTWMFGVTL WEMFTYGQEP WIGLNGSQIL HKIDKEGERL PRPEDCPQDI
YNVMVQCWAH KPEDRPTFVA LRDFLLEAQP TDMRALQDFE EPDKLHIQMN DVITVIEGRA
ENYWWRGQNT RTLCVGPFPR NVVTSVAGLS AQDISQPLQN SFIHTGHGDS DPRHCWGFPD
RIDELYLGNP MDPPDLLSVE LSTSRPPQHL GGVKKPTYDP VSEDQDPLSS DFKRLGLRKP
GLPRGLWLAK PSARVPGTKA SRGSGAEVTL IDFGEEPVVP ALRPCAPSLA QLAMDACSLL
DETPPQSPTR ALPRPLHPTP VVDWDARPLP PPPAYDDVAQ DEDDFEICSI NSTLVGAGVP
AGPSQGQTNY AFVPEQARPP PPLEDNLFLP PQGGGKPPSS AQTAEIFQAL QQECMRQLQA
PAGSPAPSPS PGGDDKPQVP PRVPIPPRPT RPHVQLSPAP PGEEETSQWP GPASPPRVPP
REPLSPQGSR TPSPLVPPGS SPLPPRLSSS PGKTMPTTQS FASDPKYATP QVIQAPGPRA
GPCILPIVRD GKKVSSTHYY LLPERPSYLE RYQRFLREAQ SPEEPTPLPV PLLLPPPSTP
APAAPTATVR PMPQAALDPK ANFSTNNSNP GARPPPPRAT ARLPQRGCPG DGPEAGRPAD
KIQMAMVHGV TTEECQAALQ CHGWSVQRAA QYLKVEQLFG LGLRPRGECH KVLEMFDWNL
EQAGCHLLGS WGPAHHKR
