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 27-MAR-2024, entry version 219. DE RecName: Full=Homeodomain-interacting protein kinase 2; DE Short=hHIPk2; DE EC=2.7.11.1 {ECO:0000269|PubMed:33591310}; 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 FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH DAZAP2 AND SIAH1, RP SUBCELLULAR LOCATION, UBIQUITINATION BY SIAH1, AND MUTAGENESIS OF LYS-228. RX PubMed=33591310; DOI=10.1093/nar/gkab084; RA Liebl M.C., Moehlenbrink J., Becker H., Raddatz G., Abdeen S.K., RA Aqeilan R.I., Lyko F., Hofmann T.G.; RT "DAZAP2 acts as specifier of the p53 response to DNA damage."; RL Nucleic Acids Res. 49:2759-2776(2021). RN [44] 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, ZBTB4 and DAZAP2. Inhibits CC cell growth and promotes apoptosis through the activation of p53/TP53 CC both at the transcription level and at the protein level (by CC phosphorylation and indirect acetylation). The phosphorylation of CC p53/TP53 may be mediated by a p53/TP53-HIPK2-AXIN1 complex. Involved in CC the response to hypoxia by acting as a transcriptional co-suppressor of CC HIF1A. Mediates transcriptional activation of TP73. In response to CC TGFB, cooperates with DAXX to activate JNK. Negative regulator through CC phosphorylation and subsequent proteasomal degradation of CTNNB1 and CC the antiapoptotic factor CTBP1. In the Wnt/beta-catenin signaling CC pathway acts as an intermediate kinase between MAP3K7/TAK1 and NLK to CC promote the proteasomal degradation of MYB. Phosphorylates CBX4 upon CC DNA damage and promotes its E3 SUMO-protein ligase activity. Activates CC CREB1 and ATF1 transcription factors by phosphorylation in response to CC genotoxic stress. In response to DNA damage, stabilizes PML by CC phosphorylation. PML, HIPK2 and FBXO3 may act synergically to activate CC p53/TP53-dependent transactivation. Promotes angiogenesis, and is CC involved in 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. In response to DNA damage, phosphorylates CC DAZAP2 which localizes DAZAP2 to the nucleus, reduces interaction of CC DAZAP2 with HIPK2 and prevents DAZAP2-dependent ubiquitination of HIPK2 CC by E3 ubiquitin-protein ligase SIAH1 and subsequent proteasomal CC degradation (PubMed:33591310). 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 ECO:0000269|PubMed:33591310}. 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:33591310}; 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:33591310}; 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). Interacts with DAZAP2; the interaction results in CC phosphorylation of DAZAP2 which causes localization of DAZAP2 to the CC nucleus, reduces interaction of DAZAP2 with HIPK2 and prevents DAZAP2- CC dependent degradation of HIPK2 (PubMed:33591310). Interacts with SIAH1; CC the interaction is promoted by DAZAP2 and results in SIAH1-mediated CC ubiquitination and subsequent proteasomal degradation of HIPK2 CC (PubMed:33591310). {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 ECO:0000269|PubMed:33591310}. 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 ECO:0000269|PubMed:33591310}. Cytoplasm {ECO:0000269|PubMed:33591310}. CC Cytoplasm, Stress granule {ECO:0000269|PubMed:33591310}. CC Note=Concentrated in PML/POD/ND10 nuclear bodies. Small amounts are CC 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, ECO:0000269|PubMed:33591310}. 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="https://atlasgeneticsoncology.org/gene/40824/HIPK2"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; 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; 192. DR CORUM; Q9H2X6; -. DR DIP; DIP-31716N; -. DR ELM; Q9H2X6; -. DR IntAct; Q9H2X6; 29. 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; 4 sites, 1 O-linked glycan (4 sites). 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; 9606-ENSP00000385571; -. DR PeptideAtlas; 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; 412 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 AGR; HGNC:14402; -. 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; GHNTTNT; -. DR OrthoDB; 3095114at2759; -. 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 432 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 209 other cell types or tissues. DR ExpressionAtlas; Q9H2X6; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA: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; IDA:UniProtKB. 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; IPI: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:0030330; P:DNA damage response, signal transduction by p53 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:0040029; P:epigenetic regulation of gene expression; TAS:Reactome. DR GO; GO:0030218; P:erythrocyte differentiation; ISS:UniProtKB. DR GO; GO:0001654; P:eye development; ISS:UniProtKB. DR GO; GO:0010467; P:gene expression; IEA:Ensembl. 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:0060425; P:lung morphogenesis; 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; IDA:UniProtKB. 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: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; 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:0003016; P:respiratory system process; IEA:Ensembl. 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:0030878; P:thyroid gland development; IEA:Ensembl. 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 CDD; cd14227; STKc_HIPK2; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR24058; DUAL SPECIFICITY PROTEIN KINASE; 1. DR PANTHER; PTHR24058:SF53; HOMEODOMAIN-INTERACTING PROTEIN KINASE 2; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; Q9H2X6; HS. 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 600..800 FT /note="Interaction with DAZAP2" FT /evidence="ECO:0000269|PubMed:33591310" 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, EP300 and DAZAP2." 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 ECO:0000269|PubMed:33591310" 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 FT 359-AAF-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 //