Human Gene HIPK2 (uc003vvf.4) Description and Page Index
  Description: Homo sapiens homeodomain interacting protein kinase 2 (HIPK2), transcript variant 1, mRNA.
RefSeq Summary (NM_022740): This gene encodes a conserved serine/threonine kinase that is a member of the homeodomain-interacting protein kinase family. The encoded protein interacts with homeodomain transcription factors and many other transcription factors such as p53, and can function as both a corepressor and a coactivator depending on the transcription factor and its subcellular localization. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011].
Transcript (Including UTRs)
   Position: hg19 chr7:139,246,316-139,477,693 Size: 231,378 Total Exon Count: 15 Strand: -
Coding Region
   Position: hg19 chr7:139,257,673-139,477,422 Size: 219,750 Coding Exon Count: 15 

Page IndexSequence and LinksUniProtKB CommentsGenetic AssociationsMalaCardsCTD
Gene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther Species
GO AnnotationsmRNA DescriptionsPathwaysOther NamesModel InformationMethods
Data last updated: 2013-06-14

-  Sequence and Links to Tools and Databases
Genomic Sequence (chr7:139,246,316-139,477,693)mRNA (may differ from genome)Protein (1198 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
BioGPSCGAPEnsemblEntrez GeneExonPrimerGeneCards
OMIMPubMedReactomeStanford SOURCEUniProtKBWikipedia

-  Comments and Description Text from UniProtKB
DESCRIPTION: RecName: Full=Homeodomain-interacting protein kinase 2; Short=hHIPk2; EC=;
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 phoyphorylation- mediated subnuclear localization shifting of PDX1. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis.
CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
SUBUNIT: 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.
SUBCELLULAR LOCATION: Nucleus, PML body. Cytoplasm. Note=Concentrated in PML/POD/ND10 nuclear bodies. Small amounts are cytoplasmic.
TISSUE SPECIFICITY: Highly expressed in heart, muscle and kidney. Weakly expressed in a ubiquitous way. Down-regulated in several thyroid and breast tumors.
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. Consitutively 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.
PTM: Phosphorylated on tyrosines (By similarity). Autophosphorylated.
PTM: 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.
PTM: 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.
PTM: 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.
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 (PubMed:20514025).
SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. HIPK subfamily.
SIMILARITY: Contains 1 protein kinase domain.

-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): HIPK2
CDC HuGE Published Literature: HIPK2
Positive Disease Associations: Diabetes Mellitus, Type 2
Related Studies:
  1. Diabetes Mellitus, Type 2
    Laura J Scott et al. Science (New York, N.Y.) 2007, A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants., Science (New York, N.Y.). [PubMed 17463248]

-  MalaCards Disease Associations
  MalaCards Gene Search: HIPK2
Diseases sorted by gene-association score: hypoxia (8), pilocytic astrocytoma (3)

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

+  Common Gene Haplotype Alleles
  Press "+" in the title bar above to open this section.

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 79.50 RPKM in Brain - Substantia nigra
Total median expression: 792.76 RPKM

View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -154.02271-0.568 Picture PostScript Text
3' UTR -3883.0011357-0.342 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR011009 - Kinase-like_dom
IPR000719 - Prot_kinase_cat_dom
IPR017441 - Protein_kinase_ATP_BS
IPR002290 - Ser/Thr_dual-sp_kinase_dom
IPR008271 - Ser/Thr_kinase_AS

Pfam Domains:
PF00069 - Protein kinase domain
PF06293 - Lipopolysaccharide kinase (Kdo/WaaP) family
PF07714 - Protein tyrosine kinase

SCOP Domains:
56112 - Protein kinase-like (PK-like)

ModBase Predicted Comparative 3D Structure on Q9H2X6
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologNo orthologGenome BrowserNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
  Protein Sequence   

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0000166 nucleotide binding
GO:0001102 RNA polymerase II activating transcription factor binding
GO:0001105 RNA polymerase II transcription coactivator activity
GO:0003714 transcription corepressor activity
GO:0004672 protein kinase activity
GO:0004674 protein serine/threonine kinase activity
GO:0005515 protein binding
GO:0005524 ATP binding
GO:0016301 kinase activity
GO:0016740 transferase activity
GO:0046332 SMAD binding
GO:0046790 virion binding

Biological Process:
GO:0000122 negative regulation of transcription from RNA polymerase II promoter
GO:0001654 eye development
GO:0001934 positive regulation of protein phosphorylation
GO:0006351 transcription, DNA-templated
GO:0006355 regulation of transcription, DNA-templated
GO:0006366 transcription from RNA polymerase II promoter
GO:0006468 protein phosphorylation
GO:0006915 apoptotic process
GO:0006974 cellular response to DNA damage stimulus
GO:0006978 DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator
GO:0007179 transforming growth factor beta receptor signaling pathway
GO:0007224 smoothened signaling pathway
GO:0007628 adult walking behavior
GO:0008284 positive regulation of cell proliferation
GO:0008344 adult locomotory behavior
GO:0009952 anterior/posterior pattern specification
GO:0010842 retina layer formation
GO:0016310 phosphorylation
GO:0018105 peptidyl-serine phosphorylation
GO:0018107 peptidyl-threonine phosphorylation
GO:0019048 modulation by virus of host morphology or physiology
GO:0030182 neuron differentiation
GO:0030218 erythrocyte differentiation
GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway
GO:0030514 negative regulation of BMP signaling pathway
GO:0030578 PML body organization
GO:0032092 positive regulation of protein binding
GO:0042771 intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
GO:0043388 positive regulation of DNA binding
GO:0043524 negative regulation of neuron apoptotic process
GO:0045766 positive regulation of angiogenesis
GO:0045893 positive regulation of transcription, DNA-templated
GO:0045944 positive regulation of transcription from RNA polymerase II promoter
GO:0046330 positive regulation of JNK cascade
GO:0048596 embryonic camera-type eye morphogenesis
GO:0050882 voluntary musculoskeletal movement
GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity
GO:0051726 regulation of cell cycle
GO:0060059 embryonic retina morphogenesis in camera-type eye
GO:0060235 lens induction in camera-type eye
GO:0060395 SMAD protein signal transduction
GO:0061072 iris morphogenesis
GO:0071456 cellular response to hypoxia
GO:0097193 intrinsic apoptotic signaling pathway
GO:1901796 regulation of signal transduction by p53 class mediator
GO:2000059 negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process

Cellular Component:
GO:0005634 nucleus
GO:0005654 nucleoplasm
GO:0005737 cytoplasm
GO:0016604 nuclear body
GO:0016605 PML body
GO:0090575 RNA polymerase II transcription factor complex

-  Descriptions from all associated GenBank mRNAs
  LF213901 - JP 2014500723-A/21404: Polycomb-Associated Non-Coding RNAs.
AF208291 - Homo sapiens protein kinase HIPK2 mRNA, complete cds.
AF326592 - Homo sapiens homeodomain interacting protein kinase 2 (HIPK2) mRNA, complete cds.
MA449478 - JP 2018138019-A/21404: Polycomb-Associated Non-Coding RNAs.
AF207702 - Homo sapiens homeodomain-interacting protein kinase 2 (HIPK2) mRNA, complete cds, alternatively spliced.
LF207092 - JP 2014500723-A/14595: Polycomb-Associated Non-Coding RNAs.
MA442669 - JP 2018138019-A/14595: Polycomb-Associated Non-Coding RNAs.
BC041926 - Homo sapiens cDNA clone IMAGE:5300349.
BX647377 - Homo sapiens mRNA; cDNA DKFZp686K02111 (from clone DKFZp686K02111).
AL833223 - Homo sapiens mRNA; cDNA DKFZp667I137 (from clone DKFZp667I137).
JD464455 - Sequence 445479 from Patent EP1572962.
JD413587 - Sequence 394611 from Patent EP1572962.
JD375121 - Sequence 356145 from Patent EP1572962.
JD554376 - Sequence 535400 from Patent EP1572962.
JD549852 - Sequence 530876 from Patent EP1572962.
JD404229 - Sequence 385253 from Patent EP1572962.
JD126276 - Sequence 107300 from Patent EP1572962.
JD396459 - Sequence 377483 from Patent EP1572962.
AF055019 - Homo sapiens clone 24670 mRNA sequence.
BC045719 - Homo sapiens cDNA clone IMAGE:4797596.
AK074291 - Homo sapiens cDNA FLJ23711 fis, clone HEP12371.
JD477785 - Sequence 458809 from Patent EP1572962.
JD387019 - Sequence 368043 from Patent EP1572962.
JD311130 - Sequence 292154 from Patent EP1572962.
JD234956 - Sequence 215980 from Patent EP1572962.
JD338491 - Sequence 319515 from Patent EP1572962.
JD108822 - Sequence 89846 from Patent EP1572962.
JD279107 - Sequence 260131 from Patent EP1572962.
JD389207 - Sequence 370231 from Patent EP1572962.
JD113584 - Sequence 94608 from Patent EP1572962.
JD534368 - Sequence 515392 from Patent EP1572962.
JD454502 - Sequence 435526 from Patent EP1572962.
JD158632 - Sequence 139656 from Patent EP1572962.
BC043184 - Homo sapiens cDNA clone IMAGE:5288067.
BC043652 - Homo sapiens cDNA clone IMAGE:5284663.
LF207091 - JP 2014500723-A/14594: Polycomb-Associated Non-Coding RNAs.
JD044156 - Sequence 25180 from Patent EP1572962.
JD395309 - Sequence 376333 from Patent EP1572962.
JD326841 - Sequence 307865 from Patent EP1572962.
LF361835 - JP 2014500723-A/169338: Polycomb-Associated Non-Coding RNAs.
JD309079 - Sequence 290103 from Patent EP1572962.
JD433058 - Sequence 414082 from Patent EP1572962.
JD178463 - Sequence 159487 from Patent EP1572962.
JD343267 - Sequence 324291 from Patent EP1572962.
JD343283 - Sequence 324307 from Patent EP1572962.
BC168360 - Synthetic construct Homo sapiens clone IMAGE:100068256, MGC:195873 HIPK2 protein (HIPK2) mRNA, encodes complete protein.
LF361836 - JP 2014500723-A/169339: Polycomb-Associated Non-Coding RNAs.
LF361837 - JP 2014500723-A/169340: Polycomb-Associated Non-Coding RNAs.
AF111850 - Homo sapiens PRO0593 mRNA, complete cds.
LF361843 - JP 2014500723-A/169346: Polycomb-Associated Non-Coding RNAs.
MA442668 - JP 2018138019-A/14594: Polycomb-Associated Non-Coding RNAs.
MA597412 - JP 2018138019-A/169338: Polycomb-Associated Non-Coding RNAs.
MA597413 - JP 2018138019-A/169339: Polycomb-Associated Non-Coding RNAs.
MA597414 - JP 2018138019-A/169340: Polycomb-Associated Non-Coding RNAs.
MA597420 - JP 2018138019-A/169346: Polycomb-Associated Non-Coding RNAs.
JD485557 - Sequence 466581 from Patent EP1572962.
JD300218 - Sequence 281242 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  Reactome (by CSHL, EBI, and GO)

Protein Q9H2X6 (Reactome details) participates in the following event(s):

R-HSA-8878050 HIPK2 phosphorylates RUNX1 and EP300
R-HSA-8878054 HIPK2 phosphorylates RUNX1
R-HSA-3215251 TP53INP1 and HIPK2 bind TP53
R-HSA-6799409 HIPK2 phosphorylates TP53
R-HSA-8939243 RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known
R-HSA-6804756 Regulation of TP53 Activity through Phosphorylation
R-HSA-8878171 Transcriptional regulation by RUNX1
R-HSA-5633007 Regulation of TP53 Activity
R-HSA-212436 Generic Transcription Pathway
R-HSA-3700989 Transcriptional Regulation by TP53
R-HSA-73857 RNA Polymerase II Transcription
R-HSA-74160 Gene expression (Transcription)

-  Other Names for This Gene
  Alternate Gene Symbols: HIPK2_HUMAN, NM_022740, NP_073577, Q75MR7, Q8WWI4, Q9H2X6, Q9H2Y1
UCSC ID: uc003vvf.4
RefSeq Accession: NM_022740
Protein: Q9H2X6 (aka HIPK2_HUMAN or HIK2_HUMAN)

-  Gene Model Information
category: coding nonsense-mediated-decay: no RNA accession: NM_022740.4
exon count: 15CDS single in 3' UTR: no RNA size: 15245
ORF size: 3597CDS single in intron: no Alignment % ID: 100.00
txCdsPredict score: 7231.00frame shift in genome: no % Coverage: 99.87
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: no # AT/AC introns 0
selenocysteine: no end bleed into intron: 0# strange splices: 0
Click here for a detailed description of the fields of the table above.

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.