HIPK2 (homeodomain interacting protein kinase 2)

2010-03-01   Dirk Sombroek , Thomas G Hofmann 

Deutsches Krebsforschungszentrum (dkfz.), Cellular Senescence Unit A210, Cell, Tumor Biology Program, Heidelberg, Germany





Zhang et al. (2005) reported 13 exons that span around 60 kb; however, up to 15 exons are listed in different databases.


Around 15 kb mRNA (full-length); 3594 bp open reading frame.
At least two alternative transcripts.
Entrez Nucleotide:
[NM_022740.4] Homo sapiens HIPK2, transcript variant 1; 15245 bp linear mRNA; full-length isoform,
[NM_001113239.2] Homo sapiens HIPK2, transcript variant 2; 15164 bp linear mRNA; this variant lacks an internal segment in the CDS, the resulting isoform is shorter.
UniProtHB/Swiss-Prot [Q9H2X6]:
[Q9H2X6-1] full-length isoform (1),
[Q9H2X6-2] isoform (2),
[Q9H2X6-3] isoform (3).
Ensemble Gene [ENSG00000064393]; 4 transcripts:
HIPK2-001 [ENST00000406875]; 15049 bp linear mRNA; 1198 amino acids,
HIPK2-002 [ENST00000428878]; 3969 bp linear mRNA; 1171 amino acids,
HIPK2-201 [ENST00000263551]; 14953 bp linear mRNA; 1198 amino acids,
HIPK2-202 [ENST00000342645]; 2757 bp linear mRNA; 918 amino acids.


Nothing known.



HIPK2 is a protein kinase of 1198 amino acids (131 kDa); posttranslational modifications: phosphorylation, ubiquitination, sumoylation at K25, caspase cleavage at D916 and D977.
Contains several motifs and domains (from N- to C-terminus): a nuclear localisation signal (NLS)1 (97-157), a kinase domain (192-520), an interaction domain for homeodomain transcription factors (583-798), a NLS2 (780-840) and a NLS3 within a speckle-retention signal (SRS) (860-967), a PEST sequence (839-934) and an autoinhibitory domain (935-1050).


HIPK2 is ubiquitously expressed (high mRNA levels in neuronal tissues, heart, muscle and kidney); but barely detectable at protein levels in unstressed cells. Protein levels increase upon genotoxic stress.


Mainly nuclear localisation, in nuclear bodies; but also found in nucleoplasm and cytoplasm.


HIPK2 is a potential tumour suppressor; in vivo data suggest at least a role as an haploinsufficient tumour suppressor in the skin of mice.
HIPK2 is a protein kinase that interacts with numerous transcription factors (such as p53, AML1(RUNX1), PAX6, c-MYB or NK3) as well as transcriptional regulators (such as CBP, p300, Groucho, CtBP, HMGA1 or Smads). In this way HIPK2 can activate or repress transcription and thereby influence differentiation, development and the DNA damage response.
HIPK2 is an unstable protein in unstressed cells. It is constantly degraded via the ubiquitin-proteasome system (mediated by the E3 ubiquitin ligases SIAH1/SIAH2, WSB1 and MDM2). Various types of DNA damage (e.g. UV, IR or chemotherapeutics) lead to stabilisation of the kinase and an HIPK2-mediated induction of apoptosis or presumably also senescence.
HIPK2 can promote the apoptotic program via p53-dependent and -independent pathways through phosphorylation of p53 at Ser46 or phosphorylation of the anti-apoptotic co-repressor CtBP at Ser422 (both actions leading to the transcription of pro-apoptotic target genes).
HIPK2 plays a role in the transcriptional regulation at low oxigen concentrations (hypoxia).
Interestingly, HIPK2 also seems to have pro-survival functions, at least in dopamine neurons.


HIPK2 is conserved from flies to man.



HIPK2 is rarely mutated (2 out of 130 cases) in acute myeloid leukemia (AML) and myelodyplastic syndrome (MDS) patients. Two missense mutations (R868W and N958I) within the speckle-retention signal (SRS) were reported. These mutations led to a changed nuclear localisation of HIPK2 and a decreased transactivation potential in AML1- and p53-dependent transcription. The mutants showed dominant-negative effects (Li et al., 2007).

Implicated in

Entity name
Thyroid and breast cancer
HIPK2 is frequently inactivated by transcriptional downregulation in thyroid carcinomas (8 out of 14 cases) and breast carcinomas (8 out of 20 cases) (Pierantoni et al., 2002).
Entity name
Breast cancer
HIPK2 is inactivated on protein level by cytoplasmic relocalisation through HMGA1. Overexpression of HMGA1 was reported to inhibit p53-mediated apoptosis by removing HIPK2 from the nucleus and retaining it in the cytoplasm. Observations could be correlated with in vivo data, at least in breast cancer. WT p53-expressing breast carcinomas showed a low spontaneous apoptotic index in case of HIPK2-relocalisation (Pierantoni et al., 2007).
Entity name
Epithelial tumours (with altered beta4 integrin expression)
HIPK2 was reported to repress beta4 integrin expression and thereby beta4-mediated tumour progression in a p53-dependent manner. Beta4 overexpression correlates in vivo with a cytoplasmic relocalisation of HIPK2, at least in breast cancer: HIPK2 showed a cytoplasmic pattern in 62.5% of the beta4-positive tumours (Bon et al., 2009).
Entity name
Juvenile pilocytic astrocytomas (JPA)
Benign childhood brain tumors.
A frequent amplification of HIPK2 along with BRAF rearrangements in JPA (35 out of 53 cases) through 7q34 duplication was reported. This duplication was more specific for JPA that originated from the cerebellum or the optic chiasm. It was absent in other brain tumours. If (and how) HIPK2 contributes to JPA development is currently unclear (Jacob et al., 2009).
Entity name
Cervical cancer
Surprisingly, a significant overexpression of HIPK2 in cervical cancer was reported. But if (and how) HIPK2 contributes to the development of cervical carcinomas remains unclear. No correlation between HIPK2 expression and grade or prognosis of the disease could be demonstrated so far (Al-Beiti et al., 2008).
Entity name
AML(RUNX1)-associated leukemias
HIPK2 is inactivated on protein level by relocalisation through a PEBP2-beta-SMMHC fusion protein. Targeting of HIPK2 to cytoplasmic filaments and thereby prevention of AML1(RUNX1) activation was reported. Specifically, phosphorylation of RUNX1 and its cofactor p300 seems to be inhibited by HIPK2 relocalisation (Wee et al., 2008).


Pubmed IDLast YearTitleAuthors
169175072006Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation.Aikawa Y et al
185329672008Expression of HIPK2 in cervical cancer: correlation with clinicopathology and prognosis.Al-Beiti MA et al
195676742009Negative regulation of beta4 integrin transcription by homeodomain-interacting protein kinase 2 and p53 impairs tumor progression.Bon G et al
190434062009An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response.Calzado MA et al
158022742005Phosphorylation by the DHIPK2 protein kinase modulates the corepressor activity of Groucho.Choi CY et al
180939722008Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by WD40 repeat/SOCS box protein WSB-1.Choi DW et al
117801262002Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis.D'Orazi G et al
173323582007Homeodomain-interacting protein kinase 2 is the ionizing radiation-activated p53 serine 46 kinase and is regulated by ATM.Dauth I et al
147294692004Homeodomain-interacting protein kinase-2 activity and p53 phosphorylation are critical events for cisplatin-mediated apoptosis.Di Stefano V et al
154586482004Homeodomain-interacting protein kinase-2 regulates apoptosis in developing sensory and sympathetic neurons.Doxakis E et al
157665672005Covalent modification of human homeodomain interacting protein kinase 2 by SUMO-1 at lysine 25 affects its stability.Gresko E et al
166016782006Autoregulatory control of the p53 response by caspase-mediated processing of HIPK2.Gresko E et al
128742722003Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation.Harada J et al
117404892002Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2.Hofmann TG et al
165379182006Overlapping roles for homeodomain-interacting protein kinases hipk1 and hipk2 in the mediation of cell growth in response to morphogenetic and genotoxic signals.Isono K et al
196030272009Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours.Jacob K et al
150825312004Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK.Kanei-Ishii C et al
164072272006Phosphorylation and transactivation of Pax6 by homeodomain-interacting protein kinase 2.Kim EA et al
105359251999Covalent modification of the homeodomain-interacting protein kinase 2 (HIPK2) by the ubiquitin-like protein SUMO-1.Kim YH et al
175333752007Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1- and p53-mediated transcription.Li XL et al
190469972009Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2 suggests a novel mechanism to restrain tumor growth.Nardinocchi L et al
172903072007High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2.Pierantoni GM et al
173499592007MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis.Rinaldo C et al
112676742001Isolation and characterization of cDNAs for the protein kinase HIPK2.Wang Y et al
186950002008PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis.Wee HJ et al
176665292007HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis.Wei G et al
185367142008Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR.Winter M et al
156074272005DYRK gene structure and erythroid-restricted features of DYRK3 gene expression.Zhang D et al
171599892007Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons.Zhang J et al
145679152003Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP.Zhang Q et al

Other Information

Locus ID:

NCBI: 28996
MIM: 606868
HGNC: 14402
Ensembl: ENSG00000064393


dbSNP: 28996
ClinVar: 28996
TCGA: ENSG00000064393


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
YAP1- and WWTR1 (TAZ)-stimulated gene expressionREACTOMER-HSA-2032785
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Muscle contractionREACTOMER-HSA-397014
Cardiac conductionREACTOMER-HSA-5576891
Physiological factorsREACTOMER-HSA-5578768
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
117404892002Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2.178
173499592007MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis.70
185367142008Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR.68
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
206246372010MiR-27a modulates MDR1/P-glycoprotein expression by targeting HIPK2 in human ovarian cancer cells.57
128514042003TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity.52
224067462012A systems approach identifies HIPK2 as a key regulator of kidney fibrosis.51
129075962003PML 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.45
190434062009An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response.44
146789852003HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells.43


Dirk Sombroek ; Thomas G Hofmann

HIPK2 (homeodomain interacting protein kinase 2)

Atlas Genet Cytogenet Oncol Haematol. 2010-03-01

Online version: http://atlasgeneticsoncology.org/gene/40824/hipk2-(homeodomain-interacting-protein-kinase-2)