HIPK2_MESAU
ID HIPK2_MESAU Reviewed; 1168 AA.
AC Q9WUM7;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2002, sequence version 2.
DT 03-AUG-2022, entry version 114.
DE RecName: Full=Homeodomain-interacting protein kinase 2;
DE EC=2.7.11.1;
DE AltName: Full=Mx-interacting protein kinase;
DE AltName: Full=PKM;
GN Name=Hipk2;
OS Mesocricetus auratus (Golden hamster).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Mesocricetus.
OX NCBI_TaxID=10036;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], ENZYME ACTIVITY, AUTOPHOSPHORYLATION,
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-228.
RX PubMed=10702310; DOI=10.1074/jbc.275.10.7373;
RA Trost M., Kochs G., Haller O.;
RT "Characterization of a novel serine/threonine kinase associated with
RT nuclear bodies.";
RL J. Biol. Chem. 275:7373-7377(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, INTERACTION WITH UBL1,
RP MUTAGENESIS OF LYS-228, AND FUNCTION.
RX PubMed=12565818; DOI=10.1016/s0014-4827(02)00025-3;
RA Engelhardt O.G., Boutell C., Orr A., Ullrich E., Haller O., Everett R.D.;
RT "The homeodomain-interacting kinase PKM (HIPK-2) modifies ND10 through both
RT its kinase domain and a SUMO-1 interaction motif and alters the
RT posttranslational modification of PML.";
RL Exp. Cell Res. 283:36-50(2003).
RN [3]
RP INTERACTION WITH TP73; TP53 AND TP63, SUBCELLULAR LOCATION, 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).
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 (By
CC similarity). {ECO:0000250, ECO:0000269|PubMed:11925430,
CC ECO:0000269|PubMed:12565818}.
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:10702310};
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:10702310};
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 (By similarity). {ECO:0000250|UniProtKB:Q9H2X6,
CC ECO:0000250|UniProtKB:Q9QZR5}.
CC -!- SUBCELLULAR LOCATION: Nucleus, PML body {ECO:0000269|PubMed:10702310,
CC ECO:0000269|PubMed:11925430, ECO:0000269|PubMed:12565818}. Cytoplasm
CC {ECO:0000250}.
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. Sumoylation on Lys-32 is promoted by the E3
CC SUMO-protein ligase CBX4 (By similarity). {ECO:0000250}.
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 (By similarity). {ECO:0000250}.
CC -!- PTM: Cleaved at Asp-895 and Asp-956 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.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. HIPK subfamily. {ECO:0000305}.
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DR EMBL; AF144573; AAD31319.2; -; mRNA.
DR RefSeq; NP_001268561.1; NM_001281632.1.
DR AlphaFoldDB; Q9WUM7; -.
DR SMR; Q9WUM7; -.
DR STRING; 10036.XP_005085823.1; -.
DR GeneID; 101842840; -.
DR CTD; 28996; -.
DR eggNOG; KOG0667; Eukaryota.
DR OrthoDB; 59821at2759; -.
DR Proteomes; UP000189706; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
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 Apoptosis; ATP-binding; Cytoplasm; DNA damage; Isopeptide bond; Kinase;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transcription; Transcription regulation;
KW Transferase; Tumor suppressor; Ubl conjugation.
FT CHAIN 1..1168
FT /note="Homeodomain-interacting protein kinase 2"
FT /id="PRO_0000085996"
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:0000250"
FT REGION 539..816
FT /note="Interaction with SKI and SMAD1"
FT /evidence="ECO:0000250"
FT REGION 724..869
FT /note="Interaction with POU4F1"
FT /evidence="ECO:0000250"
FT REGION 746..848
FT /note="Interaction with CTBP1"
FT /evidence="ECO:0000250"
FT REGION 759..869
FT /note="Interaction with HMGA1"
FT /evidence="ECO:0000250"
FT REGION 764..820
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 812..907
FT /note="Interaction with TP53 and TP73"
FT /evidence="ECO:0000269|PubMed:11925430"
FT REGION 845..952
FT /note="Localization to nuclear speckles"
FT /evidence="ECO:0000250"
FT REGION 845..952
FT /note="Required for localization to nuclear speckles"
FT /evidence="ECO:0000250"
FT REGION 845..879
FT /note="Interaction with UBE2I"
FT /evidence="ECO:0000250"
FT REGION 854..876
FT /note="Interaction with UBL1"
FT /evidence="ECO:0000269|PubMed:12565818"
FT REGION 856..880
FT /note="SUMO interaction motifs (SIM); required for nuclear
FT localization and kinase activity"
FT /evidence="ECO:0000250"
FT REGION 894..936
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 907..1022
FT /note="Interaction with AXIN1"
FT /evidence="ECO:0000250"
FT REGION 956..1168
FT /note="Autoinhibitory domain (AID)"
FT /evidence="ECO:0000250"
FT REGION 960..1030
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 774..777
FT /note="Nuclear localization signal 1 (NLS1)"
FT /evidence="ECO:0000250"
FT MOTIF 804..807
FT /note="Nuclear localization signal 2 (NLS2)"
FT /evidence="ECO:0000250"
FT COMPBIAS 764..805
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 894..928
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 962..1030
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 895..896
FT /note="Cleavage; by CASP6"
FT /evidence="ECO:0000250"
FT SITE 956..957
FT /note="Cleavage; by CASP6"
FT /evidence="ECO:0000250"
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"
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 607
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 641
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 660
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 787
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 799
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 906
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 963
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 1014
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 1125
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QZR5"
FT MOD_RES 1158
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:0000250"
FT CROSSLNK 32
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9H2X6"
FT CROSSLNK 925
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q9H2X6"
FT CROSSLNK 945
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q9H2X6"
FT CROSSLNK 1161
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
FT MUTAGEN 228
FT /note="K->W: Abolishes enzymatic activity. Diffuse nuclear
FT staining."
FT /evidence="ECO:0000269|PubMed:10702310,
FT ECO:0000269|PubMed:12565818"
SQ SEQUENCE 1168 AA; 127641 MW; BA1DF9C43B117F09 CRC64;
MAPVYEGMAS HVQVFSPHTL QSSAFCSVKK LKVEPSSNWD MTGYGSHSKL CSQSKNIPPS
QPASTTVSTS LPIPNPSLPY EQTIIFPGST 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 NCLDDMAQVS
MTTDLEGSDM LVEKADRREF IDLLKKMLTI DADKRITPIE TLNHPFVTMT HLLDFPHSTH
VKSCFQNMEI CKRRVNMYDT VNQSKTPFIT HVAPSTSTNL TMTFNNQLTT VHNQPSAASM
AAVAQRSMPL QTGTAQICAR PDPFQQALIV CPPGFQGLQA SPSKHAGYSV RMENAVPIVT
QAPGAQPLQI QPGLLAQAWP GGAQQILLPP AWQQLTGVAT HTSVQHAAVI PETMAGTQQL
ADWRNTHAHG SHYNPIMQQP TLLTGHVTLP AAQPLNVGVA HVMRQQPTST TSSRKSKQHQ
PSMRNVSTCE VTSSQSTSSP QRSKRVKENT PPRCAMVHSS PACSTSVTCG WGDVASSTTR
ERQRQTIVIP DTPSPTVSVI TISSDTDEEE EQKHAPTSTV SKQRKNVISC VTVHDSPYSD
SSSNTSPYSV QQRTGHNGTN TLDTKGALEN HCTGNPRTII VPPLKTQASE VLVECDSLGP
AVSTGHHSSS FKCKSSSTVT STSGHSSGSS SGAIAYRQQR PGPHFQQQQP LNLSQAQPHM
ATDRTGSHRR QQAYITPTMA QAPYTFPHNS PSHGTVHPHL AAAAHLPTQP HLYTYTAPTA
LGSTGTVAHL VASQGSARHT VQHTAYPASI VHQVPVSMGP RVLPSPTIHP SQYPAQFAHQ
TYISASPAST VYTGYPLSPA KVNQYPYI
