Written | 2010-03 | Dirk Sombroek, Thomas G Hofmann |
Deutsches Krebsforschungszentrum (dkfz.), Cellular Senescence Unit A210, Cell, Tumor Biology Program, Heidelberg, Germany |
Identity |
Alias (NCBI) | DKFZp686K02111 | FLJ23711 | hHIPk2 | PRO0593 |
HGNC (Hugo) | HIPK2 |
HGNC Previous name | homeodomain-interacting protein kinase 2 |
LocusID (NCBI) | 28996 |
Atlas_Id | 40824 |
Location | 7q34 [Link to chromosome band 7q34] |
Location_base_pair | Starts at 139561570 and ends at 139777998 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping HIPK2.png] |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
ACTB (7p22.1) / HIPK2 (7q34) | HIPK2 (7q34) / ADCK2 (7q34) | HIPK2 (7q34) / DENND2A (7q34) | |
HIPK2 (7q34) / GRM8 (7q31.33) | HIPK2 (7q34) / HIPK2 (7q34) | HIPK2 (7q34) / KCNJ12 (17p11.2) | |
HIPK2 (7q34) / MYCBP2 (13q22.3) | SQSTM1 (5q35.3) / HIPK2 (7q34) | YBX3 (12p13.2) / HIPK2 (7q34) | |
DNA/RNA |
Description | Zhang et al. (2005) reported 13 exons that span around 60 kb; however, up to 15 exons are listed in different databases. |
Transcription | 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. |
Pseudogene | Nothing known. |
Protein |
Description | 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). |
Expression | 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. |
Localisation | Mainly nuclear localisation, in nuclear bodies; but also found in nucleoplasm and cytoplasm. |
Function | 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. |
Homology | HIPK2 is conserved from flies to man. |
Mutations |
Somatic | 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 |
Note | |
Entity | Thyroid and breast cancer |
Oncogenesis | 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 | Breast cancer |
Oncogenesis | 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 | Epithelial tumours (with altered beta4 integrin expression) |
Oncogenesis | 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 | Juvenile pilocytic astrocytomas (JPA) |
Note | Benign childhood brain tumors. |
Disease | 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 | Cervical cancer |
Note | 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 | AML(RUNX1)-associated leukemias |
Oncogenesis | 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). |
Bibliography |
Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation. |
Aikawa Y, Nguyen LA, Isono K, Takakura N, Tagata Y, Schmitz ML, Koseki H, Kitabayashi I. |
EMBO J. 2006 Sep 6;25(17):3955-65. Epub 2006 Aug 17. |
PMID 16917507 |
Expression of HIPK2 in cervical cancer: correlation with clinicopathology and prognosis. |
Al-Beiti MA, Lu X. |
Aust N Z J Obstet Gynaecol. 2008 Jun;48(3):329-36. |
PMID 18532967 |
Negative regulation of beta4 integrin transcription by homeodomain-interacting protein kinase 2 and p53 impairs tumor progression. |
Bon G, Di Carlo SE, Folgiero V, Avetrani P, Lazzari C, D'Orazi G, Brizzi MF, Sacchi A, Soddu S, Blandino G, Mottolese M, Falcioni R. |
Cancer Res. 2009 Jul 15;69(14):5978-86. Epub 2009 Jun 30. |
PMID 19567674 |
An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. |
Calzado MA, de la Vega L, Moller A, Bowtell DD, Schmitz ML. |
Nat Cell Biol. 2009 Jan;11(1):85-91. Epub 2008 Nov 30. |
PMID 19043406 |
Phosphorylation by the DHIPK2 protein kinase modulates the corepressor activity of Groucho. |
Choi CY, Kim YH, Kim YO, Park SJ, Kim EA, Riemenschneider W, Gajewski K, Schulz RA, Kim Y. |
J Biol Chem. 2005 Jun 3;280(22):21427-36. Epub 2005 Mar 30. |
PMID 15802274 |
Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by WD40 repeat/SOCS box protein WSB-1. |
Choi DW, Seo YM, Kim EA, Sung KS, Ahn JW, Park SJ, Lee SR, Choi CY. |
J Biol Chem. 2008 Feb 22;283(8):4682-9. Epub 2007 Dec 19. |
PMID 18093972 |
Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. |
D'Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S, Gostissa M, Coen S, Marchetti A, Del Sal G, Piaggio G, Fanciulli M, Appella E, Soddu S. |
Nat Cell Biol. 2002 Jan;4(1):11-9. |
PMID 11780126 |
Homeodomain-interacting protein kinase 2 is the ionizing radiation-activated p53 serine 46 kinase and is regulated by ATM. |
Dauth I, Kruger J, Hofmann TG. |
Cancer Res. 2007 Mar 1;67(5):2274-9. |
PMID 17332358 |
Homeodomain-interacting protein kinase-2 activity and p53 phosphorylation are critical events for cisplatin-mediated apoptosis. |
Di Stefano V, Rinaldo C, Sacchi A, Soddu S, D'Orazi G. |
Exp Cell Res. 2004 Feb 15;293(2):311-20. |
PMID 14729469 |
Homeodomain-interacting protein kinase-2 regulates apoptosis in developing sensory and sympathetic neurons. |
Doxakis E, Huang EJ, Davies AM. |
Curr Biol. 2004 Oct 5;14(19):1761-5. |
PMID 15458648 |
Covalent modification of human homeodomain interacting protein kinase 2 by SUMO-1 at lysine 25 affects its stability. |
Gresko E, Moller A, Roscic A, Schmitz ML. |
Biochem Biophys Res Commun. 2005 Apr 22;329(4):1293-9. |
PMID 15766567 |
Autoregulatory control of the p53 response by caspase-mediated processing of HIPK2. |
Gresko E, Roscic A, Ritterhoff S, Vichalkovski A, del Sal G, Schmitz ML. |
EMBO J. 2006 May 3;25(9):1883-94. Epub 2006 Apr 6. |
PMID 16601678 |
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 MM, Kim Y, Ishii S. |
J Biol Chem. 2003 Oct 3;278(40):38998-9005. Epub 2003 Jul 21. |
PMID 12874272 |
Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. |
Hofmann TG, Moller A, Sirma H, Zentgraf H, Taya Y, Droge W, Will H, Schmitz ML. |
Nat Cell Biol. 2002 Jan;4(1):1-10. |
PMID 11740489 |
Overlapping roles for homeodomain-interacting protein kinases hipk1 and hipk2 in the mediation of cell growth in response to morphogenetic and genotoxic signals. |
Isono K, Nemoto K, Li Y, Takada Y, Suzuki R, Katsuki M, Nakagawara A, Koseki H. |
Mol Cell Biol. 2006 Apr;26(7):2758-71. |
PMID 16537918 |
Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. |
Jacob K, Albrecht S, Sollier C, Faury D, Sader E, Montpetit A, Serre D, Hauser P, Garami M, Bognar L, Hanzely Z, Montes JL, Atkinson J, Farmer JP, Bouffet E, Hawkins C, Tabori U, Jabado N. |
Br J Cancer. 2009 Aug 18;101(4):722-33. Epub 2009 Jul 14. |
PMID 19603027 |
Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK. |
Kanei-Ishii C, Ninomiya-Tsuji J, Tanikawa J, Nomura T, Ishitani T, Kishida S, Kokura K, Kurahashi T, Ichikawa-Iwata E, Kim Y, Matsumoto K, Ishii S. |
Genes Dev. 2004 Apr 1;18(7):816-29. |
PMID 15082531 |
Phosphorylation and transactivation of Pax6 by homeodomain-interacting protein kinase 2. |
Kim EA, Noh YT, Ryu MJ, Kim HT, Lee SE, Kim CH, Lee C, Kim YH, Choi CY. |
J Biol Chem. 2006 Mar 17;281(11):7489-97. Epub 2006 Jan 9. |
PMID 16407227 |
Covalent modification of the homeodomain-interacting protein kinase 2 (HIPK2) by the ubiquitin-like protein SUMO-1. |
Kim YH, Choi CY, Kim Y. |
Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12350-5. |
PMID 10535925 |
Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1- and p53-mediated transcription. |
Li XL, Arai Y, Harada H, Shima Y, Yoshida H, Rokudai S, Aikawa Y, Kimura A, Kitabayashi I. |
Oncogene. 2007 Nov 8;26(51):7231-9. Epub 2007 May 28. |
PMID 17533375 |
Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2 suggests a novel mechanism to restrain tumor growth. |
Nardinocchi L, Puca R, Guidolin D, Belloni AS, Bossi G, Michiels C, Sacchi A, Onisto M, D'Orazi G. |
Biochim Biophys Acta. 2009 Feb;1793(2):368-77. Epub 2008 Nov 6. |
PMID 19046997 |
High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2. |
Pierantoni GM, Rinaldo C, Mottolese M, Di Benedetto A, Esposito F, Soddu S, Fusco A. |
J Clin Invest. 2007 Mar;117(3):693-702. Epub 2007 Feb 8. |
PMID 17290307 |
MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis. |
Rinaldo C, Prodosmo A, Mancini F, Iacovelli S, Sacchi A, Moretti F, Soddu S. |
Mol Cell. 2007 Mar 9;25(5):739-50. |
PMID 17349959 |
Isolation and characterization of cDNAs for the protein kinase HIPK2. |
Wang Y, Hofmann TG, Runkel L, Haaf T, Schaller H, Debatin K, Hug H. |
Biochim Biophys Acta. 2001 Mar 19;1518(1-2):168-72. |
PMID 11267674 |
PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis. |
Wee HJ, Voon DC, Bae SC, Ito Y. |
Blood. 2008 Nov 1;112(9):3777-87. Epub 2008 Aug 11. |
PMID 18695000 |
HIPK2 represses beta-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis. |
Wei G, Ku S, Ma GK, Saito S, Tang AA, Zhang J, Mao JH, Appella E, Balmain A, Huang EJ. |
Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13040-5. Epub 2007 Jul 31. |
PMID 17666529 |
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 TG. |
Nat Cell Biol. 2008 Jul;10(7):812-24. Epub 2008 Jun 8. |
PMID 18536714 |
DYRK gene structure and erythroid-restricted features of DYRK3 gene expression. |
Zhang D, Li K, Erickson-Miller CL, Weiss M, Wojchowski DM. |
Genomics. 2005 Jan;85(1):117-30. |
PMID 15607427 |
Essential function of HIPK2 in TGFbeta-dependent survival of midbrain dopamine neurons. |
Zhang J, Pho V, Bonasera SJ, Holtzman J, Tang AT, Hellmuth J, Tang S, Janak PH, Tecott LH, Huang EJ. |
Nat Neurosci. 2007 Jan;10(1):77-86. Epub 2006 Dec 10. |
PMID 17159989 |
Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. |
Zhang Q, Yoshimatsu Y, Hildebrand J, Frisch SM, Goodman RH. |
Cell. 2003 Oct 17;115(2):177-86. |
PMID 14567915 |
Citation |
This paper should be referenced as such : |
Sombroek, D ; Hofmann, TG |
HIPK2 (homeodomain interacting protein kinase 2) |
Atlas Genet Cytogenet Oncol Haematol. 2010;14(12):1141-1144. |
Free journal version : [ pdf ] [ DOI ] |
Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ] |
t(1;9)(p13;p12) PAX5/HIPK1
|
Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ] |
t(7;7)(q31;q34) HIPK2/GRM8
t(7;13)(q34;q22) HIPK2/MYCBP2 |
External links |
REVIEW articles | automatic search in PubMed |
Last year publications | automatic search in PubMed |
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