HIPK2_HUMAN
ID HIPK2_HUMAN Reviewed; 1198 AA.
AC Q9H2X6; Q75MR7; Q8WWI4; Q9H2Y1;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 06-JUN-2002, sequence version 2.
DT 03-AUG-2022, entry version 210.
DE RecName: Full=Homeodomain-interacting protein kinase 2;
DE Short=hHIPk2;
DE EC=2.7.11.1;
GN Name=HIPK2;
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), SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND MUTAGENESIS OF LYS-228.
RC TISSUE=Liver, and Testis;
RX PubMed=11267674; DOI=10.1016/s0167-4781(00)00308-0;
RA Wang Y., Hofmann T.G., Runkel L., Haaf T., Schaller H., Debatin K.-M.,
RA Hug H.;
RT "Isolation and characterization of cDNAs for the protein kinase HIPK2.";
RL Biochim. Biophys. Acta 1518:168-172(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Frontal cortex;
RA Stukart G.C., Dias-Neto E.;
RT "Sequencing of hHIPk2, a human homolog of mouse homeodomain interacting
RT protein kinase 2.";
RL Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 8-1198 (ISOFORM 2).
RA Pierantoni G.M., Benvenuto G., Chiariotti L., Fusco A.;
RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP INTERACTION WITH TRADD.
RX PubMed=11032752; DOI=10.1006/bbrc.2000.3700;
RA Li X., Wang Y., Debatin K.-M., Hug H.;
RT "The serine/threonine kinase HIPK2 interacts with TRADD, but not with CD95
RT or TNF-R1 in 293T cells.";
RL Biochem. Biophys. Res. Commun. 277:513-517(2000).
RN [6]
RP TISSUE SPECIFICITY.
RX PubMed=11798164; DOI=10.1006/bbrc.2001.6310;
RA Pierantoni G.M., Bulfone A., Pentimalli F., Fedele M., Iuliano R.,
RA Santoro M., Chiariotti L., Ballabio A., Fusco A.;
RT "The homeodomain-interacting protein kinase 2 gene is expressed late in
RT embryogenesis and preferentially in retina, muscle, and neural tissues.";
RL Biochem. Biophys. Res. Commun. 290:942-947(2002).
RN [7]
RP INTERACTION WITH RANBP9, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-228.
RX PubMed=12220523; DOI=10.1016/s0006-291x(02)02020-x;
RA Wang Y., Marion Schneider E., Li X., Duttenhoefer I., Debatin K.-M.,
RA Hug H.;
RT "HIPK2 associates with RanBPM.";
RL Biochem. Biophys. Res. Commun. 297:148-153(2002).
RN [8]
RP INTERACTION WITH TP73; TP53 AND TP63, MUTAGENESIS OF LYS-228, AND FUNCTION.
RX PubMed=11925430; DOI=10.1074/jbc.m200153200;
RA Kim E.-J., Park J.-S., Um S.-J.;
RT "Identification and characterization of HIPK2 interacting with p73 and
RT modulating functions of the p53 family in vivo.";
RL J. Biol. Chem. 277:32020-32028(2002).
RN [9]
RP SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION, INTERACTION WITH TP53 AND
RP CREBBP, MUTAGENESIS OF LYS-228, FUNCTION, AND INDUCTION.
RX PubMed=11740489; DOI=10.1038/ncb715;
RA Hofmann T.G., Moeller A., Sirma H., Zentgraf H., Taya Y., Droege W.,
RA Will H., Schmitz M.L.;
RT "Regulation of p53 activity by its interaction with homeodomain-interacting
RT protein kinase-2.";
RL Nat. Cell Biol. 4:1-10(2002).
RN [10]
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-228.
RX PubMed=12907596;
RA Moeller A., Sirma H., Hofmann T.G., Rueffer S., Klimczak E., Droege W.,
RA Will H., Schmitz M.L.;
RT "PML is required for homeodomain-interacting protein kinase 2 (HIPK2)-
RT mediated p53 phosphorylation and cell cycle arrest but is dispensable for
RT the formation of HIPK domains.";
RL Cancer Res. 63:4310-4314(2003).
RN [11]
RP FUNCTION, INTERACTION WITH DAXX, AND MUTAGENESIS OF LYS-228.
RX PubMed=14678985;
RA Hofmann T.G., Stollberg N., Schmitz M.L., Will H.;
RT "HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-
RT terminal kinase activation and apoptosis in human hepatoma cells.";
RL Cancer Res. 63:8271-8277(2003).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH P53DINP1.
RX PubMed=12851404; DOI=10.1074/jbc.m301979200;
RA Tomasini R., Samir A.A., Carrier A., Isnardon D., Cecchinelli B., Soddu S.,
RA Malissen B., Dagorn J.-C., Iovanna J.L., Dusetti N.J.;
RT "TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are
RT partners in regulating p53 activity.";
RL J. Biol. Chem. 278:37722-37729(2003).
RN [13]
RP FUNCTION, INTERACTION WITH SKI; SMAD1; SMAD2 AND SMAD3, AND MUTAGENESIS OF
RP LYS-228 AND 359-SER--TYR-361.
RX PubMed=12874272; DOI=10.1074/jbc.m307112200;
RA Harada J., Kokura K., Kanei-Ishii C., Nomura T., Khan M.M., Kim Y.,
RA Ishii S.;
RT "Requirement of the co-repressor homeodomain-interacting protein kinase 2
RT for ski-mediated inhibition of bone morphogenetic protein-induced
RT transcriptional activation.";
RL J. Biol. Chem. 278:38998-39005(2003).
RN [14]
RP INTERACTION WITH HANTAAN HANTAVIRUS NUCLEOPROTEIN (MICROBIAL INFECTION),
RP AND INTERACTION WITH SEOUL HANTAVIRUS NUCLEOPROTEIN (MICROBIAL INFECTION).
RX PubMed=14609633; DOI=10.1016/j.virusres.2003.09.001;
RA Lee B.H., Yoshimatsu K., Maeda A., Ochiai K., Morimatsu M., Araki K.,
RA Ogino M., Morikawa S., Arikawa J.;
RT "Association of the nucleocapsid protein of the Seoul and Hantaan
RT hantaviruses with small ubiquitin-like modifier-1-related molecules.";
RL Virus Res. 98:83-91(2003).
RN [15]
RP INTERACTION WITH SP100.
RX PubMed=14647468; DOI=10.1038/sj.onc.1207079;
RA Moeller A., Sirma H., Hofmann T.G., Staege H., Gresko E., Luedi K.S.,
RA Klimczak E., Droege W., Will H., Schmitz M.L.;
RT "Sp100 is important for the stimulatory effect of homeodomain-interacting
RT protein kinase-2 on p53-dependent gene expression.";
RL Oncogene 22:8731-8737(2003).
RN [16]
RP DESUMOYLATION.
RX PubMed=16253240; DOI=10.1016/j.febslet.2005.10.010;
RA Kim Y.H., Sung K.S., Lee S.-J., Kim Y.-O., Choi C.Y., Kim Y.;
RT "Desumoylation of homeodomain-interacting protein kinase 2 (HIPK2) through
RT the cytoplasmic-nuclear shuttling of the SUMO-specific protease SENP1.";
RL FEBS Lett. 579:6272-6278(2005).
RN [17]
RP CLEAVAGE BY CASP6 AT ASP-923 AND ASP-984.
RX PubMed=16601678; DOI=10.1038/sj.emboj.7601077;
RA Gresko E., Roscic A., Ritterhoff S., Vichalkovski A., del Sal G.,
RA Schmitz M.L.;
RT "Autoregulatory control of the p53 response by caspase-mediated processing
RT of HIPK2.";
RL EMBO J. 25:1883-1894(2006).
RN [18]
RP INTERACTION WITH CBX4, SUMOYLATION AT LYS-32, AND FUNCTION.
RX PubMed=17018294; DOI=10.1016/j.molcel.2006.08.004;
RA Roscic A., Moeller A., Calzado M.A., Renner F., Wimmer V.C., Gresko E.,
RA Luedi K.S., Schmitz M.L.;
RT "Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its
RT substrate protein HIPK2.";
RL Mol. Cell 24:77-89(2006).
RN [19]
RP FUNCTION AS HMGA1 KINASE.
RX PubMed=17960875; DOI=10.1021/pr700571d;
RA Zhang Q., Wang Y.;
RT "Homeodomain-interacting protein kinase-2 (HIPK2) phosphorylates HMGA1a at
RT Ser-35, Thr-52, and Thr-77 and modulates its DNA binding affinity.";
RL J. Proteome Res. 6:4711-4719(2007).
RN [20]
RP FUNCTION AS RUNX1 AND EP300 KINASE, AND MUTAGENESIS OF LYS-228.
RX PubMed=18695000; DOI=10.1182/blood-2008-01-134122;
RA Wee H.-J., Voon D.C.-C., Bae S.-C., Ito Y.;
RT "PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2:
RT implications for leukemogenesis.";
RL Blood 112:3777-3787(2008).
RN [21]
RP INTERACTION WITH WSB1, AND UBIQUITINATION BY WSB1.
RX PubMed=18093972; DOI=10.1074/jbc.m708873200;
RA Choi D.W., Seo Y.-M., Kim E.-A., Sung K.S., Ahn J.W., Park S.-J.,
RA Lee S.-R., Choi C.Y.;
RT "Ubiquitination and degradation of homeodomain-interacting protein kinase 2
RT by WD40 repeat/SOCS box protein WSB-1.";
RL J. Biol. Chem. 283:4682-4689(2008).
RN [22]
RP FUNCTION, AND UBIQUITINATION BY FBXO3.
RX PubMed=18809579; DOI=10.1128/mcb.00897-08;
RA Shima Y., Shima T., Chiba T., Irimura T., Pandolfi P.P., Kitabayashi I.;
RT "PML activates transcription by protecting HIPK2 and p300 from SCFFbx3-
RT mediated degradation.";
RL Mol. Cell. Biol. 28:7126-7138(2008).
RN [23]
RP INDUCTION BY DNA DAMAGE, INTERACTION WITH SIAH1, AND UBIQUITINATION BY
RP SIAH1.
RX PubMed=18536714; DOI=10.1038/ncb1743;
RA Winter M., Sombroek D., Dauth I., Moehlenbrink J., Scheuermann K.,
RA Crone J., Hofmann T.G.;
RT "Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint
RT kinases ATM and ATR.";
RL Nat. Cell Biol. 10:812-824(2008).
RN [24]
RP FUNCTION AS HIF1A TRANSCRIPTION REGULATOR AND ANGIOGENESIS PROMOTER.
RX PubMed=19046997; DOI=10.1016/j.bbamcr.2008.10.013;
RA Nardinocchi L., Puca R., Guidolin D., Belloni A.S., Bossi G., Michiels C.,
RA Sacchi A., Onisto M., D'Orazi G.;
RT "Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2
RT suggests a novel mechanism to restrain tumor growth.";
RL Biochim. Biophys. Acta 1793:368-377(2009).
RN [25]
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 FUNCTION AS PML KINASE, INTERACTION WITH PML, AND MUTAGENESIS OF LYS-228.
RX PubMed=19015637; DOI=10.1038/onc.2008.420;
RA Gresko E., Ritterhoff S., Sevilla-Perez J., Roscic A., Froebius K.,
RA Kotevic I., Vichalkovski A., Hess D., Hemmings B.A., Schmitz M.L.;
RT "PML tumor suppressor is regulated by HIPK2-mediated phosphorylation in
RT response to DNA damage.";
RL Oncogene 28:698-708(2009).
RN [27]
RP FUNCTION AS ZBTB4 KINASE, AND INTERACTION WITH ZBTB4.
RX PubMed=19448668; DOI=10.1038/onc.2009.109;
RA Yamada D., Perez-Torrado R., Filion G., Caly M., Jammart B., Devignot V.,
RA Sasai N., Ravassard P., Mallet J., Sastre-Garau X., Schmitz M.L.,
RA Defossez P.A.;
RT "The human protein kinase HIPK2 phosphorylates and downregulates the
RT methyl-binding transcription factor ZBTB4.";
RL Oncogene 28:2535-2544(2009).
RN [28]
RP INDUCTION BY ZINC DURING HYPOXIA.
RX PubMed=19714248; DOI=10.1371/journal.pone.0006819;
RA Nardinocchi L., Puca R., Sacchi A., Rechavi G., Givol D., D'Orazi G.;
RT "Targeting hypoxia in cancer cells by restoring homeodomain interacting
RT protein-kinase 2 and p53 activity and suppressing HIF-1alpha.";
RL PLoS ONE 4:E6819-E6819(2009).
RN [29]
RP FUNCTION AS PDX1 KINASE.
RX PubMed=20637728; DOI=10.1016/j.bbrc.2010.07.035;
RA An R., da Silva Xavier G., Semplici F., Vakhshouri S., Hao H.X., Rutter J.,
RA Pagano M.A., Meggio F., Pinna L.A., Rutter G.A.;
RT "Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is
RT HIPK2-dependent and affects PDX1 subnuclear localization.";
RL Biochem. Biophys. Res. Commun. 399:155-161(2010).
RN [30]
RP FUNCTION AS CTNNB1 KINASE.
RX PubMed=20307497; DOI=10.1016/j.bbrc.2010.03.099;
RA Kim E.-A., Kim J.E., Sung K.S., Choi D.W., Lee B.J., Choi C.Y.;
RT "Homeodomain-interacting protein kinase 2 (HIPK2) targets beta-catenin for
RT phosphorylation and proteasomal degradation.";
RL Biochem. Biophys. Res. Commun. 394:966-971(2010).
RN [31]
RP FUNCTION AS ATF1 KINASE, AND INTERACTION WITH ATF1.
RX PubMed=20980392; DOI=10.1242/jcs.073627;
RA Hailemariam K., Iwasaki K., Huang B.W., Sakamoto K., Tsuji Y.;
RT "Transcriptional regulation of ferritin and antioxidant genes by HIPK2
RT under genotoxic stress.";
RL J. Cell Sci. 123:3863-3871(2010).
RN [32]
RP FUNCTION AS CREB1 KINASE, AND INTERACTION WITH CREB1.
RX PubMed=20573984; DOI=10.1091/mbc.e10-01-0015;
RA Sakamoto K., Huang B.-W., Iwasaki K., Hailemariam K., Ninomiya-Tsuji J.,
RA Tsuji Y.;
RT "Regulation of genotoxic stress response by homeodomain-interacting protein
RT kinase 2 through phosphorylation of cyclic AMP response element-binding
RT protein at serine 271.";
RL Mol. Biol. Cell 21:2966-2974(2010).
RN [33]
RP SUBCELLULAR LOCATION, SUMOYLATION, NUCLEAR LOCALIZATION SIGNALS,
RP MUTAGENESIS OF LYS-803; LYS-805; ARG-833; LYS-835; 885-VAL--SER-892 AND
RP 893-ASP--GLU-899, AND INTERACTION WITH CBX4.
RX PubMed=21145359; DOI=10.1016/j.bbamcr.2010.11.022;
RA de la Vega L., Froebius K., Moreno R., Calzado M.A., Geng H., Schmitz M.L.;
RT "Control of nuclear HIPK2 localization and function by a SUMO interaction
RT motif.";
RL Biochim. Biophys. Acta 1813:283-297(2011).
RN [34]
RP SUBCELLULAR LOCATION, SUMOYLATION, FUNCTION, AND MUTAGENESIS OF
RP 885-VAL--ILE-888 AND 892-SER--ASP-895.
RX PubMed=21192925; DOI=10.1016/j.yexcr.2010.12.016;
RA Sung K.S., Lee Y.A., Kim E.T., Lee S.R., Ahn J.H., Choi C.Y.;
RT "Role of the SUMO-interacting motif in HIPK2 targeting to the PML nuclear
RT bodies and regulation of p53.";
RL Exp. Cell Res. 317:1060-1070(2011).
RN [35]
RP REVIEW ON DNA DAMAGE SIGNALING, INDUCTION BY GENOTOXIC AGENTS, AND
RP STABILIZATION BY DNA DAMAGE.
RX PubMed=18974774; DOI=10.1038/cdd.2008.154;
RA Sombroek D., Hofmann T.G.;
RT "How cells switch HIPK2 on and off.";
RL Cell Death Differ. 16:187-194(2009).
RN [36]
RP REVIEW.
RX PubMed=19788416; DOI=10.1111/j.1742-4658.2009.07331.x;
RA Bitomsky N., Hofmann T.G.;
RT "Apoptosis and autophagy: Regulation of apoptosis by DNA damage signalling
RT - roles of p53, p73 and HIPK2.";
RL FEBS J. 276:6074-6083(2009).
RN [37]
RP REVIEW AS HYPOXIA AND TP53 REGULATOR.
RX PubMed=20234185; DOI=10.4161/cc.9.7.11125;
RA Nardinocchi L., Puca R., Givol D., D'Orazi G.;
RT "HIPK2-a therapeutical target to be (re)activated for tumor suppression:
RT role in p53 activation and HIF-1? inhibition.";
RL Cell Cycle 9:1270-1275(2010).
RN [38]
RP REVIEW AS TP53 REGULATOR, AND INDUCTION BY GENOTOXIC AGENTS AND HYPOXIA.
RX PubMed=20514025; DOI=10.1038/onc.2010.183;
RA Puca R., Nardinocchi L., Givol D., D'Orazi G.;
RT "Regulation of p53 activity by HIPK2: molecular mechanisms and
RT therapeutical implications in human cancer cells.";
RL Oncogene 29:4378-4387(2010).
RN [39]
RP FUNCTION.
RX PubMed=22825850; DOI=10.1074/jbc.m112.390120;
RA Pelisch F., Pozzi B., Risso G., Munoz M.J., Srebrow A.;
RT "DNA damage-induced heterogeneous nuclear ribonucleoprotein K SUMOylation
RT regulates p53 transcriptional activation.";
RL J. Biol. Chem. 287:30789-30799(2012).
RN [40]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [41]
RP INTERACTION WITH SUMO1P1/SUMO5, AND SUBCELLULAR LOCATION.
RX PubMed=27211601; DOI=10.1038/srep26509;
RA Liang Y.C., Lee C.C., Yao Y.L., Lai C.C., Schmitz M.L., Yang W.M.;
RT "SUMO5, a novel poly-sumo isoform, regulates pml nuclear bodies.";
RL Sci. Rep. 6:26509-26509(2016).
RN [42]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-32; LYS-953 AND LYS-973, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [43]
RP VARIANTS [LARGE SCALE ANALYSIS] GLN-792 AND GLN-1027.
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).
CC -!- FUNCTION: Serine/threonine-protein kinase involved in transcription
CC regulation, p53/TP53-mediated cellular apoptosis and regulation of the
CC cell cycle. Acts as a corepressor of several transcription factors,
CC including SMAD1 and POU4F1/Brn3a and probably NK homeodomain
CC transcription factors. Phosphorylates PDX1, ATF1, PML, p53/TP53, CREB1,
CC CTBP1, CBX4, RUNX1, EP300, CTNNB1, HMGA1 and ZBTB4. Inhibits cell
CC growth and promotes apoptosis through the activation of p53/TP53 both
CC at the transcription level and at the protein level (by phosphorylation
CC and indirect acetylation). The phosphorylation of p53/TP53 may be
CC mediated by a p53/TP53-HIPK2-AXIN1 complex. Involved in the response to
CC hypoxia by acting as a transcriptional co-suppressor of HIF1A. Mediates
CC transcriptional activation of TP73. In response to TGFB, cooperates
CC with DAXX to activate JNK. Negative regulator through phosphorylation
CC and subsequent proteasomal degradation of CTNNB1 and the antiapoptotic
CC factor CTBP1. In the Wnt/beta-catenin signaling pathway acts as an
CC intermediate kinase between MAP3K7/TAK1 and NLK to promote the
CC proteasomal degradation of MYB. Phosphorylates CBX4 upon DNA damage and
CC promotes its E3 SUMO-protein ligase activity. Activates CREB1 and ATF1
CC transcription factors by phosphorylation in response to genotoxic
CC stress. In response to DNA damage, stabilizes PML by phosphorylation.
CC PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53-
CC dependent transactivation. Promotes angiogenesis, and is involved in
CC erythroid differentiation, especially during fetal liver
CC erythropoiesis. Phosphorylation of RUNX1 and EP300 stimulates EP300
CC transcription regulation activity. Triggers ZBTB4 protein degradation
CC in response to DNA damage. Modulates HMGA1 DNA-binding affinity. In
CC response to high glucose, triggers phosphorylation-mediated subnuclear
CC localization shifting of PDX1. Involved in the regulation of eye size,
CC lens formation and retinal lamination during late embryogenesis.
CC {ECO:0000269|PubMed:11740489, ECO:0000269|PubMed:11925430,
CC ECO:0000269|PubMed:12851404, ECO:0000269|PubMed:12874272,
CC ECO:0000269|PubMed:14678985, ECO:0000269|PubMed:17018294,
CC ECO:0000269|PubMed:17960875, ECO:0000269|PubMed:18695000,
CC ECO:0000269|PubMed:18809579, ECO:0000269|PubMed:19015637,
CC ECO:0000269|PubMed:19046997, ECO:0000269|PubMed:19448668,
CC ECO:0000269|PubMed:20307497, ECO:0000269|PubMed:20573984,
CC ECO:0000269|PubMed:20637728, ECO:0000269|PubMed:20980392,
CC ECO:0000269|PubMed:21192925, ECO:0000269|PubMed:22825850}.
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 -!- 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;
CC -!- SUBUNIT: Interacts with CREB1, SIAH1, WSB1, CBX4, TRADD, p53/TP53,
CC TP73, TP63, CREBBP, DAXX, P53DINP1, SKI, SMAD1, SMAD2 and SMAD3, but
CC not SMAD4. Interacts with ATF1, PML, RUNX1, EP300, NKX1-2, NKX2-5,
CC UBE2I, HMGA1, CTBP1, AXIN1, NLK, MYB, POU4F1, POU4F2, POU4F3, UBE2I,
CC UBL1 and ZBTB4. Probably part of a complex consisting of p53/TP53,
CC HIPK2 and AXIN1. Interacts with SP100; positively regulates TP53-
CC dependent transcription. Interacts with SUMO1P1/SUMO5
CC (PubMed:27211601). {ECO:0000269|PubMed:11032752,
CC ECO:0000269|PubMed:11740489, ECO:0000269|PubMed:11925430,
CC ECO:0000269|PubMed:12220523, ECO:0000269|PubMed:12851404,
CC ECO:0000269|PubMed:12874272, ECO:0000269|PubMed:14647468,
CC ECO:0000269|PubMed:14678985, ECO:0000269|PubMed:17018294,
CC ECO:0000269|PubMed:18093972, ECO:0000269|PubMed:18536714,
CC ECO:0000269|PubMed:19015637, ECO:0000269|PubMed:19448668,
CC ECO:0000269|PubMed:20573984, ECO:0000269|PubMed:20980392,
CC ECO:0000269|PubMed:21145359, ECO:0000269|PubMed:27211601}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Hantaan hantavirus
CC nucleoprotein. {ECO:0000269|PubMed:14609633}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Seoul hantavirus
CC nucleoprotein. {ECO:0000269|PubMed:14609633}.
CC -!- INTERACTION:
CC Q9H2X6; P61962: DCAF7; NbExp=10; IntAct=EBI-348345, EBI-359808;
CC Q9H2X6; Q09472: EP300; NbExp=4; IntAct=EBI-348345, EBI-447295;
CC Q9H2X6; P51608: MECP2; NbExp=2; IntAct=EBI-348345, EBI-1189067;
CC Q9H2X6; Q01196: RUNX1; NbExp=4; IntAct=EBI-348345, EBI-925904;
CC Q9H2X6; Q9H3D4: TP63; NbExp=2; IntAct=EBI-348345, EBI-2337775;
CC -!- SUBCELLULAR LOCATION: Nucleus, PML body {ECO:0000269|PubMed:27211601}.
CC Cytoplasm. Note=Concentrated in PML/POD/ND10 nuclear bodies. Small
CC amounts are cytoplasmic.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Comment=Experimental confirmation may be lacking for some isoforms.;
CC Name=1;
CC IsoId=Q9H2X6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9H2X6-2; Sequence=VSP_004805, VSP_004806, VSP_004807;
CC Name=3;
CC IsoId=Q9H2X6-3; Sequence=VSP_004804;
CC -!- TISSUE SPECIFICITY: Highly expressed in heart, muscle and kidney.
CC Weakly expressed in a ubiquitous way. Down-regulated in several thyroid
CC and breast tumors. {ECO:0000269|PubMed:11267674,
CC ECO:0000269|PubMed:11798164}.
CC -!- INDUCTION: Unstable in unstressed cells but stabilized upon DNA damage.
CC Induced by UV irradiation and other genotoxic agents (adriamycin ADR,
CC cisplatin CDDP, etoposide, IR, roscovitin), thus triggering p53/TP53
CC apoptotic response. Consistutively negatively regulated by SIAH1 and
CC WSB1 through proteasomal degradation. This negative regulation is
CC impaired upon genotoxic stress. Repressed upon hypoxia (often
CC associated with tumors), through MDM2- (an E3 ubiquitin ligases)
CC mediated proteasomal degradation, thus inactivating p53/TP53 apoptotic
CC response. This hypoxia repression is reversed by zinc. The
CC stabilization mediated by DNA damage requires the damage checkpoint
CC kinases ATM and ATR. {ECO:0000269|PubMed:11740489,
CC ECO:0000269|PubMed:18536714, ECO:0000269|PubMed:18974774,
CC ECO:0000269|PubMed:19714248, ECO:0000269|PubMed:20514025}.
CC -!- PTM: Autophosphorylation at Tyr-361 in the activation loop activates
CC the kinase and promotes nuclear localization. {ECO:0000250}.
CC -!- PTM: Sumoylated. When conjugated it is directed to nuclear speckles.
CC Desumoylated by SENP1 (By similarity). Sumoylation on Lys-32 is
CC promoted by the E3 SUMO-protein ligase CBX4. {ECO:0000250,
CC ECO:0000269|PubMed:16253240, ECO:0000269|PubMed:17018294,
CC ECO:0000269|PubMed:21145359, ECO:0000269|PubMed:21192925}.
CC -!- PTM: Ubiquitinated by FBXO3, WSB1 and SIAH1, leading to rapid
CC proteasome-dependent degradation. The degradation mediated by FBXO3,
CC but not ubiquitination, is prevented in the presence of PML. The
CC degradation mediated by WSB1 and SIAH1 is reversibly reduced upon DNA
CC damage. {ECO:0000269|PubMed:18093972, ECO:0000269|PubMed:18536714,
CC ECO:0000269|PubMed:18809579}.
CC -!- PTM: Cleaved at Asp-923 and Asp-984 by CASP6 in a p53/TP53-dependent
CC manner. The cleaved form lacks the autoinhibitory C-terminal domain
CC (AID), resulting in a hyperactive kinase, which potentiates p53/TP53
CC Ser-46 phosphorylation and subsequent activation of the cell death
CC machinery. {ECO:0000269|PubMed:16601678}.
CC -!- MISCELLANEOUS: Interesting targets for cancer therapy. HIPK2
CC deregulation would end up in a multifactorial response leading to tumor
CC chemoresistance by affecting p53/TP53 activity on one hand and to
CC angiogenesis and cell proliferation by affecting HIF1A activity on the
CC other hand. May provide important insights in the process of tumor
CC progression, and may also serve as the crucial point in the diagnostic
CC and therapeutical aspects of cancer. Tumor treatment may potential be
CC improved by zinc supplementation in combination with chemotherapy to
CC address hypoxia (PubMed:20514025). {ECO:0000305|PubMed:20514025}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. HIPK subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/HIPK2ID40824ch7q34.html";
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DR EMBL; AF208291; AAG41236.1; -; mRNA.
DR EMBL; AF326592; AAL37371.1; -; mRNA.
DR EMBL; AC005531; AAS00368.1; -; Genomic_DNA.
DR EMBL; AC073184; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC006021; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC141932; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF207702; AAG35710.1; -; mRNA.
DR CCDS; CCDS75666.1; -. [Q9H2X6-3]
DR CCDS; CCDS75667.1; -. [Q9H2X6-1]
DR RefSeq; NP_001106710.1; NM_001113239.2. [Q9H2X6-3]
DR RefSeq; NP_073577.3; NM_022740.4. [Q9H2X6-1]
DR PDB; 6P5S; X-ray; 2.19 A; A=177-547.
DR PDB; 7NCF; X-ray; 2.72 A; A=183-547.
DR PDBsum; 6P5S; -.
DR PDBsum; 7NCF; -.
DR AlphaFoldDB; Q9H2X6; -.
DR SMR; Q9H2X6; -.
DR BioGRID; 118815; 184.
DR CORUM; Q9H2X6; -.
DR DIP; DIP-31716N; -.
DR ELM; Q9H2X6; -.
DR IntAct; Q9H2X6; 27.
DR MINT; Q9H2X6; -.
DR STRING; 9606.ENSP00000385571; -.
DR BindingDB; Q9H2X6; -.
DR ChEMBL; CHEMBL4576; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q9H2X6; -.
DR GuidetoPHARMACOLOGY; 2034; -.
DR GlyGen; Q9H2X6; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9H2X6; -.
DR PhosphoSitePlus; Q9H2X6; -.
DR BioMuta; HIPK2; -.
DR DMDM; 21431782; -.
DR EPD; Q9H2X6; -.
DR jPOST; Q9H2X6; -.
DR MassIVE; Q9H2X6; -.
DR MaxQB; Q9H2X6; -.
DR PaxDb; Q9H2X6; -.
DR PeptideAtlas; Q9H2X6; -.
DR PRIDE; Q9H2X6; -.
DR ProteomicsDB; 80628; -. [Q9H2X6-1]
DR ProteomicsDB; 80629; -. [Q9H2X6-2]
DR ProteomicsDB; 80630; -. [Q9H2X6-3]
DR TopDownProteomics; Q9H2X6-2; -. [Q9H2X6-2]
DR Antibodypedia; 9921; 365 antibodies from 33 providers.
DR DNASU; 28996; -.
DR Ensembl; ENST00000406875.8; ENSP00000385571.3; ENSG00000064393.16. [Q9H2X6-1]
DR Ensembl; ENST00000428878.6; ENSP00000413724.2; ENSG00000064393.16. [Q9H2X6-3]
DR GeneID; 28996; -.
DR KEGG; hsa:28996; -.
DR MANE-Select; ENST00000406875.8; ENSP00000385571.3; NM_022740.5; NP_073577.3.
DR UCSC; uc003vvd.5; human. [Q9H2X6-1]
DR CTD; 28996; -.
DR DisGeNET; 28996; -.
DR GeneCards; HIPK2; -.
DR HGNC; HGNC:14402; HIPK2.
DR HPA; ENSG00000064393; Tissue enriched (brain).
DR MIM; 606868; gene.
DR neXtProt; NX_Q9H2X6; -.
DR OpenTargets; ENSG00000064393; -.
DR PharmGKB; PA29291; -.
DR VEuPathDB; HostDB:ENSG00000064393; -.
DR eggNOG; KOG0667; Eukaryota.
DR GeneTree; ENSGT00940000157742; -.
DR HOGENOM; CLU_003045_1_0_1; -.
DR InParanoid; Q9H2X6; -.
DR OMA; THSKVYN; -.
DR OrthoDB; 59821at2759; -.
DR PhylomeDB; Q9H2X6; -.
DR TreeFam; TF105417; -.
DR BRENDA; 2.7.11.1; 2681.
DR PathwayCommons; Q9H2X6; -.
DR Reactome; R-HSA-2032785; YAP1- and WWTR1 (TAZ)-stimulated gene expression.
DR Reactome; R-HSA-3899300; SUMOylation of transcription cofactors.
DR Reactome; R-HSA-5578768; Physiological factors.
DR Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR Reactome; R-HSA-8939243; RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known.
DR Reactome; R-HSA-9022692; Regulation of MECP2 expression and activity.
DR SignaLink; Q9H2X6; -.
DR SIGNOR; Q9H2X6; -.
DR BioGRID-ORCS; 28996; 10 hits in 358 CRISPR screens.
DR ChiTaRS; HIPK2; human.
DR GeneWiki; HIPK2; -.
DR GenomeRNAi; 28996; -.
DR Pharos; Q9H2X6; Tchem.
DR PRO; PR:Q9H2X6; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; Q9H2X6; protein.
DR Bgee; ENSG00000064393; Expressed in medial globus pallidus and 207 other tissues.
DR ExpressionAtlas; Q9H2X6; baseline and differential.
DR Genevisible; Q9H2X6; HS.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0016604; C:nuclear body; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; ISS:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:BHF-UCL.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISS:BHF-UCL.
DR GO; GO:0046332; F:SMAD binding; IPI:UniProtKB.
DR GO; GO:0003713; F:transcription coactivator activity; IEA:Ensembl.
DR GO; GO:0003714; F:transcription corepressor activity; IDA:UniProtKB.
DR GO; GO:0046790; F:virion binding; IPI:UniProtKB.
DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl.
DR GO; GO:0009952; P:anterior/posterior pattern specification; IEA:Ensembl.
DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl.
DR GO; GO:0071456; P:cellular response to hypoxia; TAS:UniProtKB.
DR GO; GO:0006978; P:DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator; IDA:BHF-UCL.
DR GO; GO:0048596; P:embryonic camera-type eye morphogenesis; IEA:Ensembl.
DR GO; GO:0060059; P:embryonic retina morphogenesis in camera-type eye; IEA:Ensembl.
DR GO; GO:0030218; P:erythrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0001654; P:eye development; ISS:UniProtKB.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; NAS:UniProtKB.
DR GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IBA:GO_Central.
DR GO; GO:0061072; P:iris morphogenesis; IEA:Ensembl.
DR GO; GO:0060235; P:lens induction in camera-type eye; IEA:Ensembl.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IMP:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:2000059; P:negative regulation of ubiquitin-dependent protein catabolic process; IMP:FlyBase.
DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0030182; P:neuron differentiation; IEA:Ensembl.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISS:BHF-UCL.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISS:BHF-UCL.
DR GO; GO:0030578; P:PML body organization; TAS:UniProtKB.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IDA:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:Ensembl.
DR GO; GO:0043388; P:positive regulation of DNA binding; IEA:Ensembl.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; ISS:BHF-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IMP:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; ISS:BHF-UCL.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:BHF-UCL.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; TAS:UniProtKB.
DR GO; GO:1901796; P:regulation of signal transduction by p53 class mediator; TAS:Reactome.
DR GO; GO:0010842; P:retina layer formation; IEA:Ensembl.
DR GO; GO:0060395; P:SMAD protein signal transduction; IDA:UniProtKB.
DR GO; GO:0007224; P:smoothened signaling pathway; IBA:GO_Central.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0050882; P:voluntary musculoskeletal movement; IEA:Ensembl.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; ATP-binding; Cytoplasm;
KW DNA damage; Host-virus interaction; Isopeptide bond; Kinase;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transcription; Transcription regulation;
KW Transferase; Ubl conjugation.
FT CHAIN 1..1198
FT /note="Homeodomain-interacting protein kinase 2"
FT /id="PRO_0000085995"
FT DOMAIN 199..527
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 97..230
FT /note="Transcriptional corepression"
FT /evidence="ECO:0000250"
FT REGION 189..520
FT /note="Interaction with DAXX"
FT /evidence="ECO:0000269|PubMed:14678985"
FT REGION 539..844
FT /note="Interaction with SKI and SMAD1"
FT /evidence="ECO:0000269|PubMed:12874272"
FT REGION 752..897
FT /note="Interaction with POU4F1"
FT /evidence="ECO:0000250"
FT REGION 774..876
FT /note="Interaction with CTBP1"
FT /evidence="ECO:0000250"
FT REGION 787..897
FT /note="Interaction with HMGA1"
FT /evidence="ECO:0000250"
FT REGION 792..847
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 846..941
FT /note="Interaction with TP53 and TP73"
FT /evidence="ECO:0000269|PubMed:11925430"
FT REGION 864..885
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 873..980
FT /note="Required for localization to nuclear speckles"
FT /evidence="ECO:0000250"
FT REGION 873..907
FT /note="Interaction with UBE2I"
FT /evidence="ECO:0000250"
FT REGION 884..908
FT /note="SUMO interaction motifs (SIM); required for nuclear
FT localization and kinase activity"
FT REGION 935..1049
FT /note="Interaction with AXIN1"
FT /evidence="ECO:0000250"
FT REGION 984..1198
FT /note="Autoinhibitory domain (AID)"
FT REGION 990..1056
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 802..805
FT /note="Nuclear localization signal 1 (NLS1)"
FT MOTIF 832..835
FT /note="Nuclear localization signal 2 (NLS2)"
FT COMPBIAS 792..833
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 324
FT /note="Proton acceptor"
FT /evidence="ECO:0000305"
FT BINDING 205..213
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT BINDING 228
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT SITE 923..924
FT /note="Cleavage; by CASP6"
FT SITE 984..985
FT /note="Cleavage; by CASP6"
FT MOD_RES 16
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 118
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 135
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 141
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 252
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 273
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 361
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 441
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 482
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 517
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 566
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 634
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 668
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 687
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 815
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 827
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 934
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 992
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 1041
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 1155
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 1188
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT CROSSLNK 32
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000269|PubMed:17018294"
FT CROSSLNK 32
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 953
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 973
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 1191
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
FT VAR_SEQ 595..621
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_004804"
FT VAR_SEQ 808..907
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_004805"
FT VAR_SEQ 989..1018
FT /note="VNTSHHSSSYKSKSSSNVTSTSGHSSGSSS -> GNLGPGQGRNLSLESGFP
FT AFLLLEMLLYGS (in isoform 2)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_004806"
FT VAR_SEQ 1019..1198
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_004807"
FT VARIANT 792
FT /note="R -> Q (in dbSNP:rs56132157)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040547"
FT VARIANT 1027
FT /note="R -> Q (in dbSNP:rs35255718)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040548"
FT MUTAGEN 228
FT /note="K->A: Locates in the nucleoplasm, no effect on
FT interaction with RANBP9, but loss of kinase activity toward
FT PML, RUNX1 and EP300."
FT /evidence="ECO:0000269|PubMed:11267674,
FT ECO:0000269|PubMed:11740489, ECO:0000269|PubMed:11925430,
FT ECO:0000269|PubMed:12220523, ECO:0000269|PubMed:12874272,
FT ECO:0000269|PubMed:12907596, ECO:0000269|PubMed:14678985,
FT ECO:0000269|PubMed:18695000, ECO:0000269|PubMed:19015637"
FT MUTAGEN 228
FT /note="K->R: Abolishes enzymatic activity, no effect on
FT interaction with TP53 and TP73 or on BMP-induced
FT transcriptional activation. Enhances BMP-induced
FT transcriptional activation; when associated with 359-AAF-
FT 361."
FT /evidence="ECO:0000269|PubMed:11267674,
FT ECO:0000269|PubMed:11740489, ECO:0000269|PubMed:11925430,
FT ECO:0000269|PubMed:12220523, ECO:0000269|PubMed:12874272,
FT ECO:0000269|PubMed:12907596, ECO:0000269|PubMed:14678985,
FT ECO:0000269|PubMed:18695000, ECO:0000269|PubMed:19015637"
FT MUTAGEN 359..361
FT /note="STY->AAF: Enhances BMP-induced transcriptional
FT activation; when associated with R-228."
FT /evidence="ECO:0000269|PubMed:12874272"
FT MUTAGEN 803
FT /note="K->A: Impaired nuclear localization; when associated
FT with A-805."
FT /evidence="ECO:0000269|PubMed:21145359"
FT MUTAGEN 805
FT /note="K->A: Impaired nuclear localization; when associated
FT with A-803."
FT /evidence="ECO:0000269|PubMed:21145359"
FT MUTAGEN 833
FT /note="R->A: Impaired nuclear localization."
FT /evidence="ECO:0000269|PubMed:21145359"
FT MUTAGEN 835
FT /note="K->E: Impaired nuclear localization."
FT /evidence="ECO:0000269|PubMed:21145359"
FT MUTAGEN 885..892
FT /note="VSVITISS->KFMHFHRM: Loss of SUMO and CBX4
FT interaction, and impaired nuclear and PML-nuclear bodies
FT localization."
FT /evidence="ECO:0000269|PubMed:21145359"
FT MUTAGEN 885..888
FT /note="VSVI->KSAK: Loss of SUMO interaction, and impaired
FT nuclear and PML-nuclear bodies localization."
FT /evidence="ECO:0000269|PubMed:21192925"
FT MUTAGEN 892..895
FT /note="SDTD->ADTA: Loss of SUMO interaction, and impaired
FT nuclear and PML-nuclear bodies localization."
FT /evidence="ECO:0000269|PubMed:21192925"
FT MUTAGEN 893..899
FT /note="DTDEEEE->NFNQQQQ: Loss of SUMO and CBX4 interaction,
FT and impaired nuclear and PML-nuclear bodies localization."
FT /evidence="ECO:0000269|PubMed:21145359"
FT CONFLICT 33
FT /note="I -> V (in Ref. 1; AAG41236)"
FT /evidence="ECO:0000305"
FT CONFLICT 59
FT /note="L -> P (in Ref. 1; AAG41236)"
FT /evidence="ECO:0000305"
FT CONFLICT 64
FT /note="T -> S (in Ref. 1; AAG41236)"
FT /evidence="ECO:0000305"
FT CONFLICT 169
FT /note="S -> F (in Ref. 4; AAG35710)"
FT /evidence="ECO:0000305"
FT CONFLICT 187
FT /note="V -> S (in Ref. 4; AAG35710)"
FT /evidence="ECO:0000305"
FT CONFLICT 202
FT /note="L -> S (in Ref. 4; AAG35710)"
FT /evidence="ECO:0000305"
FT CONFLICT 233
FT /note="H -> R (in Ref. 1; AAG41236)"
FT /evidence="ECO:0000305"
FT CONFLICT 471
FT /note="N -> I (in Ref. 2; AAL37371)"
FT /evidence="ECO:0000305"
FT CONFLICT 669
FT /note="P -> S (in Ref. 4; AAG35710)"
FT /evidence="ECO:0000305"
FT CONFLICT 711
FT /note="T -> N (in Ref. 4; AAG35710)"
FT /evidence="ECO:0000305"
FT CONFLICT 717..719
FT /note="PPA -> SPT (in Ref. 4; AAG35710)"
FT /evidence="ECO:0000305"
FT CONFLICT 724
FT /note="T -> D (in Ref. 4; AAG35710)"
FT /evidence="ECO:0000305"
FT STRAND 191..193
FT /evidence="ECO:0007829|PDB:7NCF"
FT STRAND 198..206
FT /evidence="ECO:0007829|PDB:6P5S"
FT STRAND 212..218
FT /evidence="ECO:0007829|PDB:6P5S"
FT STRAND 224..229
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 239..251
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 255..258
FT /evidence="ECO:0007829|PDB:6P5S"
FT STRAND 263..268
FT /evidence="ECO:0007829|PDB:6P5S"
FT STRAND 273..278
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 284..290
FT /evidence="ECO:0007829|PDB:6P5S"
FT TURN 291..293
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 298..317
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 327..329
FT /evidence="ECO:0007829|PDB:6P5S"
FT STRAND 330..334
FT /evidence="ECO:0007829|PDB:6P5S"
FT TURN 335..337
FT /evidence="ECO:0007829|PDB:6P5S"
FT STRAND 338..344
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 365..367
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 370..374
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 382..396
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 406..417
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 422..425
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 431..433
FT /evidence="ECO:0007829|PDB:6P5S"
FT STRAND 435..439
FT /evidence="ECO:0007829|PDB:6P5S"
FT STRAND 441..443
FT /evidence="ECO:0007829|PDB:6P5S"
FT STRAND 446..448
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 451..458
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 473..476
FT /evidence="ECO:0007829|PDB:6P5S"
FT TURN 477..480
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 487..507
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 512..514
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 518..522
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 525..528
FT /evidence="ECO:0007829|PDB:6P5S"
FT HELIX 530..534
FT /evidence="ECO:0007829|PDB:6P5S"
SQ SEQUENCE 1198 AA; 130966 MW; 6022D5710E8D2D93 CRC64;
MAPVYEGMAS HVQVFSPHTL QSSAFCSVKK LKIEPSSNWD MTGYGSHSKV YSQSKNIPLS
QPATTTVSTS LPVPNPSLPY EQTIVFPGST GHIVVTSASS TSVTGQVLGG PHNLMRRSTV
SLLDTYQKCG LKRKSEEIEN TSSVQIIEEH PPMIQNNASG ATVATATTST ATSKNSGSNS
EGDYQLVQHE VLCSMTNTYE VLEFLGRGTF GQVVKCWKRG TNEIVAIKIL KNHPSYARQG
QIEVSILARL STESADDYNF VRAYECFQHK NHTCLVFEML EQNLYDFLKQ NKFSPLPLKY
IRPVLQQVAT ALMKLKSLGL IHADLKPENI MLVDPSRQPY RVKVIDFGSA SHVSKAVCST
YLQSRYYRAP EIILGLPFCE AIDMWSLGCV IAELFLGWPL YPGASEYDQI RYISQTQGLP
AEYLLSAGTK TTRFFNRDTD SPYPLWRLKT PDDHEAETGI KSKEARKYIF NCLDDMAQVN
MTTDLEGSDM LVEKADRREF IDLLKKMLTI DADKRITPIE TLNHPFVTMT HLLDFPHSTH
VKSCFQNMEI CKRRVNMYDT VNQSKTPFIT HVAPSTSTNL TMTFNNQLTT VHNQAPSSTS
ATISLANPEV SILNYPSTLY QPSAASMAAV AQRSMPLQTG TAQICARPDP FQQALIVCPP
GFQGLQASPS KHAGYSVRME NAVPIVTQAP GAQPLQIQPG LLAQQAWPSG TQQILLPPAW
QQLTGVATHT SVQHATVIPE TMAGTQQLAD WRNTHAHGSH YNPIMQQPAL LTGHVTLPAA
QPLNVGVAHV MRQQPTSTTS SRKSKQHQSS VRNVSTCEVS SSQAISSPQR SKRVKENTPP
RCAMVHSSPA CSTSVTCGWG DVASSTTRER QRQTIVIPDT PSPTVSVITI SSDTDEEEEQ
KHAPTSTVSK QRKNVISCVT VHDSPYSDSS SNTSPYSVQQ RAGHNNANAF DTKGSLENHC
TGNPRTIIVP PLKTQASEVL VECDSLVPVN TSHHSSSYKS KSSSNVTSTS GHSSGSSSGA
ITYRQQRPGP HFQQQQPLNL SQAQQHITTD RTGSHRRQQA YITPTMAQAP YSFPHNSPSH
GTVHPHLAAA AAAAHLPTQP HLYTYTAPAA LGSTGTVAHL VASQGSARHT VQHTAYPASI
VHQVPVSMGP RVLPSPTIHP SQYPAQFAHQ TYISASPAST VYTGYPLSPA KVNQYPYI
