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Q9H2X6 (HIPK2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified March 19, 2014. Version 142. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Homeodomain-interacting protein kinase 2

Short name=hHIPk2
EC=2.7.11.1
Gene names
Name:HIPK2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1198 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine-protein kinase involved in transcription regulation, p53/TP53-mediated cellular apoptosis and regulation of the cell cycle. Acts as a corepressor of several transcription factors, including SMAD1 and POU4F1/Brn3a and probably NK homeodomain transcription factors. Phosphorylates PDX1, ATF1, PML, p53/TP53, CREB1, CTBP1, CBX4, RUNX1, EP300, CTNNB1, HMGA1 and ZBTB4. Inhibits cell growth and promotes apoptosis through the activation of p53/TP53 both at the transcription level and at the protein level (by phosphorylation and indirect acetylation). The phosphorylation of p53/TP53 may be mediated by a p53/TP53-HIPK2-AXIN1 complex. Involved in the response to hypoxia by acting as a transcriptional co-suppressor of HIF1A. Mediates transcriptional activation of TP73. In response to TGFB, cooperates with DAXX to activate JNK. Negative regulator through phosphorylation and subsequent proteasomal degradation of CTNNB1 and the antiapoptotic factor CTBP1. In the Wnt/beta-catenin signaling pathway acts as an intermediate kinase between MAP3K7/TAK1 and NLK to promote the proteasomal degradation of MYB. Phosphorylates CBX4 upon DNA damage and promotes its E3 SUMO-protein ligase activity. Activates CREB1 and ATF1 transcription factors by phosphorylation in response to genotoxic stress. In response to DNA damage, stabilizes PML by phosphorylation. PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53-dependent transactivation. Promotes angiogenesis, and is involved in erythroid differentiation, especially during fetal liver erythropoiesis. Phosphorylation of RUNX1 and EP300 stimulates EP300 transcription regulation activity. Triggers ZBTB4 protein degradation in response to DNA damage. Modulates HMGA1 DNA-binding affinity. In response to high glucose, triggers phosphorylation-mediated subnuclear localization shifting of PDX1. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis. Ref.8 Ref.9 Ref.11 Ref.12 Ref.13 Ref.17 Ref.18 Ref.19 Ref.21 Ref.23 Ref.25 Ref.26 Ref.28 Ref.29 Ref.30 Ref.31 Ref.33 Ref.38

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Subunit structure

Interacts with CREB1, SIAH1, WSB1, CBX4, TRADD, p53/TP53, TP73, TP63, CREBBP, DAXX, P53DINP1, SKI, SMAD1, SMAD2 and SMAD3, but not SMAD4. Interacts with ATF1, PML, RUNX1, EP300, NKX1-2, NKX2-5, SPN/CD43, UBE2I, HMGA1, CTBP1, AXIN1, NLK, MYB, POU4F1, POU4F2, POU4F3, UBE2I, UBL1 and ZBTB4. Probably part of a complex consisting of p53/TP53, HIPK2 and AXIN1. Interacts with SP100; positively regulates TP53-dependent transcription. Ref.5 Ref.7 Ref.8 Ref.9 Ref.11 Ref.12 Ref.13 Ref.14 Ref.17 Ref.20 Ref.22 Ref.25 Ref.26 Ref.30 Ref.31 Ref.32

Subcellular location

NucleusPML body. Cytoplasm. Note: Concentrated in PML/POD/ND10 nuclear bodies. Small amounts are cytoplasmic. Ref.1 Ref.7 Ref.9 Ref.10 Ref.12 Ref.32 Ref.33

Tissue specificity

Highly expressed in heart, muscle and kidney. Weakly expressed in a ubiquitous way. Down-regulated in several thyroid and breast tumors. Ref.1 Ref.6

Induction

Unstable in unstressed cells but stabilized upon DNA damage. Induced by UV irradiation and other genotoxic agents (adriamycin ADR, cisplatin CDDP, etoposide, IR, roscovitin), thus triggering p53/TP53 apoptotic response. Consistutively negatively regulated by SIAH1 and WSB1 through proteasomal degradation. This negative regulation is impaired upon genotoxic stress. Repressed upon hypoxia (often associated with tumors), through MDM2- (an E3 ubiquitin ligases) mediated proteasomal degradation, thus inactivating p53/TP53 apoptotic response. This hypoxia repression is reversed by zinc. The stabilization mediated by DNA damage requires the damage checkpoint kinases ATM and ATR. Ref.9 Ref.22 Ref.27 Ref.34 Ref.37 Ref.39

Post-translational modification

Autophosphorylation at Tyr-361 in the activation loop activates the kinase and promotes nuclear localization.

Sumoylated. When conjugated it is directed to nuclear speckles. Desumoylated by SENP1 By similarity. Sumoylation on Lys-32 is promoted by the E3 SUMO-protein ligase CBX4. Ref.15 Ref.17 Ref.32 Ref.33

Ubiquitinated by FBXO3, WSB1 and SIAH1, leading to rapid proteasome-dependent degradation. The degradation mediated by FBXO3, but not ubiquitination, is prevented in the presence of PML. The degradation mediated by WSB1 and SIAH1 is reversibly reduced upon DNA damage. Ref.20 Ref.21 Ref.22

Cleaved at Asp-923 and Asp-984 by CASP6 in a p53/TP53-dependent manner. The cleaved form lacks the autoinhibitory C-terminal domain (AID), resulting in a hyperactive kinase, which potentiates p53/TP53 Ser-46 phosphorylation and subsequent activation of the cell death machinery. Ref.16

Miscellaneous

Interesting targets for cancer therapy. HIPK2 deregulation would end up in a multifactorial response leading to tumor chemoresistance by affecting p53/TP53 activity on one hand and to angiogenesis and cell proliferation by affecting HIF1A activity on the other hand. May provide important insights in the process of tumor progression, and may also serve as the crucial point in the diagnostic and therapeutical aspects of cancer. Tumor treatment may potential be improved by zinc supplementation in combination with chemotherapy to address hypoxia (Ref.37).

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. HIPK subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processApoptosis
DNA damage
Transcription
Transcription regulation
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator

Inferred from direct assay Ref.14. Source: BHF-UCL

PML body organization

Traceable author statement Ref.34. Source: UniProtKB

SMAD protein signal transduction

Inferred from direct assay Ref.13. Source: UniProtKB

adult walking behavior

Inferred from electronic annotation. Source: Ensembl

anterior/posterior pattern specification

Inferred from electronic annotation. Source: Ensembl

cellular response to hypoxia

Traceable author statement Ref.34. Source: UniProtKB

embryonic camera-type eye morphogenesis

Inferred from electronic annotation. Source: Ensembl

embryonic retina morphogenesis in camera-type eye

Inferred from electronic annotation. Source: Ensembl

erythrocyte differentiation

Inferred from sequence or structural similarity PubMed 20231426. Source: UniProtKB

eye development

Inferred from sequence or structural similarity PubMed 20579985. Source: UniProtKB

intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator

Traceable author statement Ref.34. Source: UniProtKB

iris morphogenesis

Inferred from electronic annotation. Source: Ensembl

lens induction in camera-type eye

Inferred from electronic annotation. Source: Ensembl

modulation by virus of host morphology or physiology

Non-traceable author statement PubMed 14990717. Source: UniProtKB

negative regulation of BMP signaling pathway

Inferred from mutant phenotype Ref.13. Source: UniProtKB

negative regulation of neuron apoptotic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

neuron differentiation

Inferred from electronic annotation. Source: Ensembl

peptidyl-serine phosphorylation

Inferred from sequence or structural similarity. Source: BHF-UCL

peptidyl-threonine phosphorylation

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of DNA binding

Inferred from electronic annotation. Source: Ensembl

positive regulation of JNK cascade

Inferred from mutant phenotype Ref.11. Source: UniProtKB

positive regulation of angiogenesis

Inferred from direct assay Ref.23. Source: UniProtKB

positive regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein binding

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of sequence-specific DNA binding transcription factor activity

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of transforming growth factor beta receptor signaling pathway

Inferred from mutant phenotype Ref.11. Source: UniProtKB

regulation of cell cycle

Traceable author statement Ref.34. Source: UniProtKB

retina layer formation

Inferred from electronic annotation. Source: Ensembl

smoothened signaling pathway

Inferred from electronic annotation. Source: Ensembl

transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: GOC

transforming growth factor beta receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

voluntary musculoskeletal movement

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentPML body

Inferred from electronic annotation. Source: UniProtKB-SubCell

centrosome

Inferred from direct assay. Source: HPA

cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

nuclear body

Inferred from direct assay Ref.13. Source: UniProtKB

nuclear membrane

Inferred from direct assay. Source: HPA

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

RNA polymerase II activating transcription factor binding

Inferred from sequence or structural similarity. Source: BHF-UCL

RNA polymerase II transcription coactivator activity

Inferred from electronic annotation. Source: Ensembl

protein serine/threonine kinase activity

Inferred from sequence or structural similarity. Source: BHF-UCL

transcription corepressor activity

Inferred from direct assay Ref.13. Source: UniProtKB

virion binding

Inferred from physical interaction PubMed 14990717. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Note: Experimental confirmation may be lacking for some isoforms.
Isoform 1 (identifier: Q9H2X6-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q9H2X6-2)

The sequence of this isoform differs from the canonical sequence as follows:
     808-907: Missing.
     989-1018: VNTSHHSSSYKSKSSSNVTSTSGHSSGSSS → GNLGPGQGRNLSLESGFPAFLLLEMLLYGS
     1019-1198: Missing.
Isoform 3 (identifier: Q9H2X6-3)

The sequence of this isoform differs from the canonical sequence as follows:
     595-621: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 11981198Homeodomain-interacting protein kinase 2
PRO_0000085995

Regions

Domain199 – 527329Protein kinase
Nucleotide binding205 – 2139ATP Probable
Region97 – 230134Transcriptional corepression By similarity
Region189 – 520332Interaction with DAXX
Region539 – 844306Interaction with SKI and SMAD1
Region752 – 897146Interaction with POU4F1 By similarity
Region774 – 876103Interaction with CTBP1 By similarity
Region787 – 897111Interaction with HMGA1 By similarity
Region802 – 8054Nuclear localization signal 1 (NLS1)
Region832 – 8354Nuclear localization signal 2 (NLS2)
Region846 – 94196Interaction with TP53 and TP73
Region873 – 980108Required for localization to nuclear speckles By similarity
Region873 – 90735Interaction with UBE2I By similarity
Region884 – 90825SUMO interaction motifs (SIM); required for nuclear localization and kinase activity
Region935 – 1049115Interaction with AXIN1 By similarity
Region984 – 1198215Autoinhibitory domain (AID)
Compositional bias1088 – 10947Poly-Ala

Sites

Active site3241Proton acceptor Probable
Binding site2281ATP Probable
Site923 – 9242Cleavage; by CASP6
Site984 – 9852Cleavage; by CASP6

Amino acid modifications

Modified residue161Phosphoserine Ref.39
Modified residue1181Phosphoserine Ref.39
Modified residue1351Phosphoserine Ref.39
Modified residue1411Phosphothreonine Ref.39
Modified residue2521Phosphothreonine Ref.39
Modified residue2731Phosphothreonine Ref.39
Modified residue3611Phosphotyrosine; by autocatalysis Ref.39
Modified residue4411Phosphoserine Ref.39
Modified residue4821Phosphothreonine Ref.39
Modified residue5171Phosphothreonine Ref.39
Modified residue5661Phosphothreonine Ref.39
Modified residue6341Phosphoserine Ref.39
Modified residue6681Phosphoserine Ref.39
Modified residue6871Phosphothreonine Ref.39
Modified residue8151Phosphoserine Ref.39
Modified residue8271Phosphoserine Ref.39
Modified residue9341Phosphoserine Ref.39
Modified residue9911Phosphothreonine Ref.39
Modified residue9921Phosphoserine
Modified residue10411Phosphoserine Ref.39
Modified residue11551Phosphoserine Ref.39
Modified residue11881Phosphoserine Ref.39
Cross-link32Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.17
Cross-link1191Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity

Natural variations

Alternative sequence595 – 62127Missing in isoform 3.
VSP_004804
Alternative sequence808 – 907100Missing in isoform 2.
VSP_004805
Alternative sequence989 – 101830VNTSH…SGSSS → GNLGPGQGRNLSLESGFPAF LLLEMLLYGS in isoform 2.
VSP_004806
Alternative sequence1019 – 1198180Missing in isoform 2.
VSP_004807
Natural variant7921R → Q. Ref.40
VAR_040547
Natural variant10271R → Q. Ref.40
VAR_040548

Experimental info

Mutagenesis2281K → A: Locates in the nucleoplasm, no effect on interaction with RANBP9, but loss of kinase activity toward PML, RUNX1 and EP300. Ref.1 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.13 Ref.19 Ref.25
Mutagenesis2281K → R: Abolishes enzymatic activity, no effect on interaction with TP53 and TP73 or on BMP-induced transcriptional activation. Enhances BMP-induced transcriptional activation; when associated with 359-AAF-361. Ref.1 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.13 Ref.19 Ref.25
Mutagenesis359 – 3613STY → AAF: Enhances BMP-induced transcriptional activation; when associated with R-228. Ref.13 Ref.39
Mutagenesis3611Y → F or A: Strongly reduced nuclear localization. Ref.39
Mutagenesis8031K → A: Impaired nuclear localization; when associated with A-805. Ref.32
Mutagenesis8051K → A: Impaired nuclear localization; when associated with A-803. Ref.32
Mutagenesis8331R → A: Impaired nuclear localization. Ref.32
Mutagenesis8351K → E: Impaired nuclear localization. Ref.32
Mutagenesis885 – 8928VSVITISS → KFMHFHRM: Loss of SUMO and CBX4 interaction, and impaired nuclear and PML-nuclear bodies localization. Ref.32
Mutagenesis885 – 8884VSVI → KSAK: Loss of SUMO interaction, and impaired nuclear and PML-nuclear bodies localization. Ref.33
Mutagenesis892 – 8954SDTD → ADTA: Loss of SUMO interaction, and impaired nuclear and PML-nuclear bodies localization. Ref.33
Mutagenesis893 – 8997DTDEEEE → NFNQQQQ: Loss of SUMO and CBX4 interaction, and impaired nuclear and PML-nuclear bodies localization. Ref.32
Sequence conflict331I → V in AAG41236. Ref.1
Sequence conflict591L → P in AAG41236. Ref.1
Sequence conflict641T → S in AAG41236. Ref.1
Sequence conflict1691S → F in AAG35710. Ref.4
Sequence conflict1871V → S in AAG35710. Ref.4
Sequence conflict2021L → S in AAG35710. Ref.4
Sequence conflict2331H → R in AAG41236. Ref.1
Sequence conflict4711N → I in AAL37371. Ref.2
Sequence conflict6691P → S in AAG35710. Ref.4
Sequence conflict7111T → N in AAG35710. Ref.4
Sequence conflict717 – 7193PPA → SPT in AAG35710. Ref.4
Sequence conflict7241T → D in AAG35710. Ref.4

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified June 6, 2002. Version 2.
Checksum: 6022D5710E8D2D93

FASTA1,198130,966
        10         20         30         40         50         60 
MAPVYEGMAS HVQVFSPHTL QSSAFCSVKK LKIEPSSNWD MTGYGSHSKV YSQSKNIPLS 

        70         80         90        100        110        120 
QPATTTVSTS LPVPNPSLPY EQTIVFPGST GHIVVTSASS TSVTGQVLGG PHNLMRRSTV 

       130        140        150        160        170        180 
SLLDTYQKCG LKRKSEEIEN TSSVQIIEEH PPMIQNNASG ATVATATTST ATSKNSGSNS 

       190        200        210        220        230        240 
EGDYQLVQHE VLCSMTNTYE VLEFLGRGTF GQVVKCWKRG TNEIVAIKIL KNHPSYARQG 

       250        260        270        280        290        300 
QIEVSILARL STESADDYNF VRAYECFQHK NHTCLVFEML EQNLYDFLKQ NKFSPLPLKY 

       310        320        330        340        350        360 
IRPVLQQVAT ALMKLKSLGL IHADLKPENI MLVDPSRQPY RVKVIDFGSA SHVSKAVCST 

       370        380        390        400        410        420 
YLQSRYYRAP EIILGLPFCE AIDMWSLGCV IAELFLGWPL YPGASEYDQI RYISQTQGLP 

       430        440        450        460        470        480 
AEYLLSAGTK TTRFFNRDTD SPYPLWRLKT PDDHEAETGI KSKEARKYIF NCLDDMAQVN 

       490        500        510        520        530        540 
MTTDLEGSDM LVEKADRREF IDLLKKMLTI DADKRITPIE TLNHPFVTMT HLLDFPHSTH 

       550        560        570        580        590        600 
VKSCFQNMEI CKRRVNMYDT VNQSKTPFIT HVAPSTSTNL TMTFNNQLTT VHNQAPSSTS 

       610        620        630        640        650        660 
ATISLANPEV SILNYPSTLY QPSAASMAAV AQRSMPLQTG TAQICARPDP FQQALIVCPP 

       670        680        690        700        710        720 
GFQGLQASPS KHAGYSVRME NAVPIVTQAP GAQPLQIQPG LLAQQAWPSG TQQILLPPAW 

       730        740        750        760        770        780 
QQLTGVATHT SVQHATVIPE TMAGTQQLAD WRNTHAHGSH YNPIMQQPAL LTGHVTLPAA 

       790        800        810        820        830        840 
QPLNVGVAHV MRQQPTSTTS SRKSKQHQSS VRNVSTCEVS SSQAISSPQR SKRVKENTPP 

       850        860        870        880        890        900 
RCAMVHSSPA CSTSVTCGWG DVASSTTRER QRQTIVIPDT PSPTVSVITI SSDTDEEEEQ 

       910        920        930        940        950        960 
KHAPTSTVSK QRKNVISCVT VHDSPYSDSS SNTSPYSVQQ RAGHNNANAF DTKGSLENHC 

       970        980        990       1000       1010       1020 
TGNPRTIIVP PLKTQASEVL VECDSLVPVN TSHHSSSYKS KSSSNVTSTS GHSSGSSSGA 

      1030       1040       1050       1060       1070       1080 
ITYRQQRPGP HFQQQQPLNL SQAQQHITTD RTGSHRRQQA YITPTMAQAP YSFPHNSPSH 

      1090       1100       1110       1120       1130       1140 
GTVHPHLAAA AAAAHLPTQP HLYTYTAPAA LGSTGTVAHL VASQGSARHT VQHTAYPASI 

      1150       1160       1170       1180       1190 
VHQVPVSMGP RVLPSPTIHP SQYPAQFAHQ TYISASPAST VYTGYPLSPA KVNQYPYI 

« Hide

Isoform 2 [UniParc].

Checksum: BA34005E15CFC5CD
Show »

FASTA918101,013
Isoform 3 [UniParc].

Checksum: C38A3241948C7D66
Show »

FASTA1,171128,158

References

« Hide 'large scale' references
[1]"Isolation and characterization of cDNAs for the protein kinase HIPK2."
Wang Y., Hofmann T.G., Runkel L., Haaf T., Schaller H., Debatin K.-M., Hug H.
Biochim. Biophys. Acta 1518:168-172(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, TISSUE SPECIFICITY, MUTAGENESIS OF LYS-228.
Tissue: Liver and Testis.
[2]"Sequencing of hHIPk2, a human homolog of mouse homeodomain interacting protein kinase 2."
Stukart G.C., Dias-Neto E.
Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
Tissue: Frontal cortex.
[3]"The DNA sequence of human chromosome 7."
Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. expand/collapse author list , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K.
Nature 424:157-164(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]Pierantoni G.M., Benvenuto G., Chiariotti L., Fusco A.
Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 8-1198 (ISOFORM 2).
[5]"The serine/threonine kinase HIPK2 interacts with TRADD, but not with CD95 or TNF-R1 in 293T cells."
Li X., Wang Y., Debatin K.-M., Hug H.
Biochem. Biophys. Res. Commun. 277:513-517(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TRADD.
[6]"The homeodomain-interacting protein kinase 2 gene is expressed late in embryogenesis and preferentially in retina, muscle, and neural tissues."
Pierantoni G.M., Bulfone A., Pentimalli F., Fedele M., Iuliano R., Santoro M., Chiariotti L., Ballabio A., Fusco A.
Biochem. Biophys. Res. Commun. 290:942-947(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[7]"HIPK2 associates with RanBPM."
Wang Y., Marion Schneider E., Li X., Duttenhoefer I., Debatin K.-M., Hug H.
Biochem. Biophys. Res. Commun. 297:148-153(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RANBP9, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-228.
[8]"Identification and characterization of HIPK2 interacting with p73 and modulating functions of the p53 family in vivo."
Kim E.-J., Park J.-S., Um S.-J.
J. Biol. Chem. 277:32020-32028(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TP73; TP53 AND TP63, MUTAGENESIS OF LYS-228, FUNCTION.
[9]"Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2."
Hofmann T.G., Moeller A., Sirma H., Zentgraf H., Taya Y., Droege W., Will H., Schmitz M.L.
Nat. Cell Biol. 4:1-10(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION, INTERACTION WITH TP53 AND CREBBP, MUTAGENESIS OF LYS-228, FUNCTION, INDUCTION.
[10]"PML is required for homeodomain-interacting protein kinase 2 (HIPK2)-mediated p53 phosphorylation and cell cycle arrest but is dispensable for the formation of HIPK domains."
Moeller A., Sirma H., Hofmann T.G., Rueffer S., Klimczak E., Droege W., Will H., Schmitz M.L.
Cancer Res. 63:4310-4314(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-228.
[11]"HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells."
Hofmann T.G., Stollberg N., Schmitz M.L., Will H.
Cancer Res. 63:8271-8277(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH DAXX, MUTAGENESIS OF LYS-228.
[12]"TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity."
Tomasini R., Samir A.A., Carrier A., Isnardon D., Cecchinelli B., Soddu S., Malissen B., Dagorn J.-C., Iovanna J.L., Dusetti N.J.
J. Biol. Chem. 278:37722-37729(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH P53DINP1.
[13]"Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation."
Harada J., Kokura K., Kanei-Ishii C., Nomura T., Khan M.M., Kim Y., Ishii S.
J. Biol. Chem. 278:38998-39005(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH SKI; SMAD1; SMAD2 AND SMAD3, MUTAGENESIS OF LYS-228 AND 359-SER--TYR-361.
[14]"Sp100 is important for the stimulatory effect of homeodomain-interacting protein kinase-2 on p53-dependent gene expression."
Moeller A., Sirma H., Hofmann T.G., Staege H., Gresko E., Luedi K.S., Klimczak E., Droege W., Will H., Schmitz M.L.
Oncogene 22:8731-8737(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SP100.
[15]"Desumoylation of homeodomain-interacting protein kinase 2 (HIPK2) through the cytoplasmic-nuclear shuttling of the SUMO-specific protease SENP1."
Kim Y.H., Sung K.S., Lee S.-J., Kim Y.-O., Choi C.Y., Kim Y.
FEBS Lett. 579:6272-6278(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: DESUMOYLATION.
[16]"Autoregulatory control of the p53 response by caspase-mediated processing of HIPK2."
Gresko E., Roscic A., Ritterhoff S., Vichalkovski A., del Sal G., Schmitz M.L.
EMBO J. 25:1883-1894(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: CLEAVAGE BY CASP6 AT ASP-923 AND ASP-984.
[17]"Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its substrate protein HIPK2."
Roscic A., Moeller A., Calzado M.A., Renner F., Wimmer V.C., Gresko E., Luedi K.S., Schmitz M.L.
Mol. Cell 24:77-89(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CBX4, SUMOYLATION AT LYS-32, FUNCTION.
[18]"Homeodomain-interacting protein kinase-2 (HIPK2) phosphorylates HMGA1a at Ser-35, Thr-52, and Thr-77 and modulates its DNA binding affinity."
Zhang Q., Wang Y.
J. Proteome Res. 6:4711-4719(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS HMGA1 KINASE.
[19]"PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis."
Wee H.-J., Voon D.C.-C., Bae S.-C., Ito Y.
Blood 112:3777-3787(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS RUNX1 AND EP300 KINASE, MUTAGENESIS OF LYS-228.
[20]"Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by WD40 repeat/SOCS box protein WSB-1."
Choi D.W., Seo Y.-M., Kim E.-A., Sung K.S., Ahn J.W., Park S.-J., Lee S.-R., Choi C.Y.
J. Biol. Chem. 283:4682-4689(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH WSB1, UBIQUITINATION BY WSB1.
[21]"PML activates transcription by protecting HIPK2 and p300 from SCFFbx3-mediated degradation."
Shima Y., Shima T., Chiba T., Irimura T., Pandolfi P.P., Kitabayashi I.
Mol. Cell. Biol. 28:7126-7138(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, UBIQUITINATION BY FBXO3.
[22]"Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR."
Winter M., Sombroek D., Dauth I., Moehlenbrink J., Scheuermann K., Crone J., Hofmann T.G.
Nat. Cell Biol. 10:812-824(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION BY DNA DAMAGE, INTERACTION WITH SIAH1, UBIQUITINATION BY SIAH1.
[23]"Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2 suggests a novel mechanism to restrain tumor growth."
Nardinocchi L., Puca R., Guidolin D., Belloni A.S., Bossi G., Michiels C., Sacchi A., Onisto M., D'Orazi G.
Biochim. Biophys. Acta 1793:368-377(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS HIF1A TRANSCRIPTION REGULATOR AND ANGIOGENESIS PROMOTER.
[24]"Large-scale proteomics analysis of the human kinome."
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H.
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[25]"PML tumor suppressor is regulated by HIPK2-mediated phosphorylation in response to DNA damage."
Gresko E., Ritterhoff S., Sevilla-Perez J., Roscic A., Froebius K., Kotevic I., Vichalkovski A., Hess D., Hemmings B.A., Schmitz M.L.
Oncogene 28:698-708(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS PML KINASE, INTERACTION WITH PML, MUTAGENESIS OF LYS-228.
[26]"The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4."
Yamada D., Perez-Torrado R., Filion G., Caly M., Jammart B., Devignot V., Sasai N., Ravassard P., Mallet J., Sastre-Garau X., Schmitz M.L., Defossez P.A.
Oncogene 28:2535-2544(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS ZBTB4 KINASE, INTERACTION WITH ZBTB4.
[27]"Targeting hypoxia in cancer cells by restoring homeodomain interacting protein-kinase 2 and p53 activity and suppressing HIF-1alpha."
Nardinocchi L., Puca R., Sacchi A., Rechavi G., Givol D., D'Orazi G.
PLoS ONE 4:E6819-E6819(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INDUCTION BY ZINC DURING HYPOXIA.
[28]"Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is HIPK2-dependent and affects PDX1 subnuclear localization."
An R., da Silva Xavier G., Semplici F., Vakhshouri S., Hao H.X., Rutter J., Pagano M.A., Meggio F., Pinna L.A., Rutter G.A.
Biochem. Biophys. Res. Commun. 399:155-161(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS PDX1 KINASE.
[29]"Homeodomain-interacting protein kinase 2 (HIPK2) targets beta-catenin for phosphorylation and proteasomal degradation."
Kim E.-A., Kim J.E., Sung K.S., Choi D.W., Lee B.J., Choi C.Y.
Biochem. Biophys. Res. Commun. 394:966-971(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS CTNNB1 KINASE.
[30]"Transcriptional regulation of ferritin and antioxidant genes by HIPK2 under genotoxic stress."
Hailemariam K., Iwasaki K., Huang B.W., Sakamoto K., Tsuji Y.
J. Cell Sci. 123:3863-3871(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS ATF1 KINASE, INTERACTION WITH ATF1.
[31]"Regulation of genotoxic stress response by homeodomain-interacting protein kinase 2 through phosphorylation of cyclic AMP response element-binding protein at serine 271."
Sakamoto K., Huang B.-W., Iwasaki K., Hailemariam K., Ninomiya-Tsuji J., Tsuji Y.
Mol. Biol. Cell 21:2966-2974(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION AS CREB1 KINASE, INTERACTION WITH CREB1.
[32]"Control of nuclear HIPK2 localization and function by a SUMO interaction motif."
de la Vega L., Froebius K., Moreno R., Calzado M.A., Geng H., Schmitz M.L.
Biochim. Biophys. Acta 1813:283-297(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, SUMOYLATION, NUCLEAR LOCALIZATION SIGNALS, MUTAGENESIS OF LYS-803; LYS-805; ARG-833; LYS-835; 885-VAL--SER-892 AND 893-ASP--GLU-899, INTERACTION WITH CBX4.
[33]"Role of the SUMO-interacting motif in HIPK2 targeting to the PML nuclear bodies and regulation of p53."
Sung K.S., Lee Y.A., Kim E.T., Lee S.R., Ahn J.H., Choi C.Y.
Exp. Cell Res. 317:1060-1070(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, SUMOYLATION, FUNCTION, MUTAGENESIS OF 885-VAL--ILE-888 AND 892-SER--ASP-895.
[34]"How cells switch HIPK2 on and off."
Sombroek D., Hofmann T.G.
Cell Death Differ. 16:187-194(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON DNA DAMAGE SIGNALING, INDUCTION BY GENOTOXIC AGENTS, STABILIZATION BY DNA DAMAGE.
[35]"Apoptosis and autophagy: Regulation of apoptosis by DNA damage signalling - roles of p53, p73 and HIPK2."
Bitomsky N., Hofmann T.G.
FEBS J. 276:6074-6083(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[36]"HIPK2-a therapeutical target to be (re)activated for tumor suppression: role in p53 activation and HIF-1? inhibition."
Nardinocchi L., Puca R., Givol D., D'Orazi G.
Cell Cycle 9:1270-1275(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW AS HYPOXIA AND TP53 REGULATOR.
[37]"Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells."
Puca R., Nardinocchi L., Givol D., D'Orazi G.
Oncogene 29:4378-4387(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW AS TP53 REGULATOR, INDUCTION BY GENOTOXIC AGENTS AND HYPOXIA.
[38]"DNA damage-induced heterogeneous nuclear ribonucleoprotein K SUMOylation regulates p53 transcriptional activation."
Pelisch F., Pozzi B., Risso G., Munoz M.J., Srebrow A.
J. Biol. Chem. 287:30789-30799(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[39]"HIPK2 catalytic activity and subcellular localization are regulated by activation-loop Y354 autophosphorylation."
Siepi F., Gatti V., Camerini S., Crescenzi M., Soddu S.
Biochim. Biophys. Acta 1833:1443-1453(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-16; SER-118; SER-135; THR-141; THR-252; THR-273; TYR-361; SER-441; THR-482; THR-517; THR-566; SER-634; SER-668; THR-687; SER-815; SER-827; SER-934; THR-991; SER-1041; SER-1155 AND SER-1188, ENZYME REGULATION, MUTAGENESIS OF TYR-361.
[40]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] GLN-792 AND GLN-1027.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF208291 mRNA. Translation: AAG41236.1.
AF326592 mRNA. Translation: AAL37371.1.
AC005531 Genomic DNA. Translation: AAS00368.1.
AC073184 Genomic DNA. No translation available.
AC006021 Genomic DNA. No translation available.
AC141932 Genomic DNA. No translation available.
AF207702 mRNA. Translation: AAG35710.1.
RefSeqNP_001106710.1. NM_001113239.2.
NP_073577.3. NM_022740.4.
UniGeneHs.731417.

3D structure databases

ProteinModelPortalQ9H2X6.
SMRQ9H2X6. Positions 125-554.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid118815. 55 interactions.
DIPDIP-31716N.
IntActQ9H2X6. 16 interactions.
MINTMINT-234689.
STRING9606.ENSP00000263551.

Chemistry

BindingDBQ9H2X6.
ChEMBLCHEMBL4576.
GuidetoPHARMACOLOGY2034.

PTM databases

PhosphoSiteQ9H2X6.

Polymorphism databases

DMDM21431782.

Proteomic databases

PaxDbQ9H2X6.
PRIDEQ9H2X6.

Protocols and materials databases

DNASU28996.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000406875; ENSP00000385571; ENSG00000064393. [Q9H2X6-1]
ENST00000428878; ENSP00000413724; ENSG00000064393. [Q9H2X6-3]
GeneID28996.
KEGGhsa:28996.
UCSCuc003vvd.4. human. [Q9H2X6-3]
uc003vvf.4. human. [Q9H2X6-1]

Organism-specific databases

CTD28996.
GeneCardsGC07M139246.
HGNCHGNC:14402. HIPK2.
HPAHPA007611.
MIM606868. gene.
neXtProtNX_Q9H2X6.
PharmGKBPA29291.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000231785.
HOVERGENHBG051908.
InParanoidQ9H2X6.
KOK08826.
OMAYSFPHNS.
OrthoDBEOG7034GK.
PhylomeDBQ9H2X6.
TreeFamTF105417.

Enzyme and pathway databases

BRENDA2.7.11.1. 2681.
SignaLinkQ9H2X6.

Gene expression databases

ArrayExpressQ9H2X6.
BgeeQ9H2X6.
CleanExHS_HIPK2.
GenevestigatorQ9H2X6.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSHIPK2. human.
GeneWikiHIPK2.
GenomeRNAi28996.
NextBio51926.
PMAP-CutDBQ9H2X6.
PROQ9H2X6.
SOURCESearch...

Entry information

Entry nameHIPK2_HUMAN
AccessionPrimary (citable) accession number: Q9H2X6
Secondary accession number(s): Q75MR7, Q8WWI4, Q9H2Y1
Entry history
Integrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: June 6, 2002
Last modified: March 19, 2014
This is version 142 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 7

Human chromosome 7: entries, gene names and cross-references to MIM