Genomes and Genes
homeodomain interacting protein kinase 2
Gene Symbol: homeodomain interacting protein kinase 2
Description: homeodomain interacting protein kinase 2
Alias: PRO0593, homeodomain-interacting protein kinase 2, hHIPk2
Products: homeodomain interacting protein kinase 2
- Kanei Ishii C, Ninomiya Tsuji J, Tanikawa J, Nomura T, Ishitani T, Kishida S, et al. Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK. Genes Dev. 2004;18:816-29 pubmed..The down-regulation of Myb by Wnt-1 signal may play an important role in a variety of developmental steps. ..
- Wang Y, Hofmann T, Runkel L, Haaf T, Schaller H, Debatin K, et al. Isolation and characterization of cDNAs for the protein kinase HIPK2. Biochim Biophys Acta. 2001;1518:168-72 pubmed..The HIPK2 gene is located on human chromosome 7q33-35 and the protein is mainly localized in the nucleus. HIPK2 has been described to play a role as a co-repressor for homeodomain transcription factors. ..
- Kim E, Noh Y, Ryu M, Kim H, Lee S, Kim C, et al. Phosphorylation and transactivation of Pax6 by homeodomain-interacting protein kinase 2. J Biol Chem. 2006;281:7489-97 pubmed..These results strongly indicate that HIPK2 is an upstream protein kinase for Pax6 and suggest that it modulates Pax6-mediated transcriptional regulation. ..
- Inoue T, Kagawa T, Inoue Mochita M, Isono K, Ohtsu N, Nobuhisa I, et al. Involvement of the Hipk family in regulation of eyeball size, lens formation and retinal morphogenesis. FEBS Lett. 2010;584:3233-8 pubmed publisher..These data indicate that Hipk1 and Hipk2 are involved in regulation of eye size, lens formation and retinal lamination during late embryogenesis. ..
- Calzado M, Renner F, Roscic A, Schmitz M. HIPK2: a versatile switchboard regulating the transcription machinery and cell death. Cell Cycle. 2007;6:139-43 pubmedb>Homeodomain interacting protein kinase 2 (HIPK2) is an evolutionary conserved serine/threonine kinase that regulates gene expression by phosphorylation of transcription factors and accessory components of the transcription machinery...
- Roscic A, Möller A, Calzado M, Renner F, Wimmer V, Gresko E, et al. Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its substrate protein HIPK2. Mol Cell. 2006;24:77-89 pubmed..Here we show that the polycomb group protein Pc2 binds to and colocalizes with homeodomain interacting protein kinase 2 (HIPK2) and serves as a SUMO E3 ligase for this kinase...
- Gresko E, Roscic A, Ritterhoff S, Vichalkovski A, Del Sal G, Schmitz M. Autoregulatory control of the p53 response by caspase-mediated processing of HIPK2. EMBO J. 2006;25:1883-94 pubmed..The active HIPK2 fragments are further degraded during the execution and termination phase of apoptosis, thus ensuring the occurrence of HIPK2 signaling only during the early phases of apoptosis induction. ..
- Hofmann T, Stollberg N, Schmitz M, Will H. HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells. Cancer Res. 2003;63:8271-7 pubmed..Taken together, our findings indicate that HIPK2 participates in the TGF-beta signaling pathway leading to JNK activation and apoptosis. ..
- Nardinocchi L, Puca R, Guidolin D, Belloni A, Bossi G, Michiels C, et al. Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2 suggests a novel mechanism to restrain tumor growth. Biochim Biophys Acta. 2009;1793:368-77 pubmed publisher..These findings provide the first evidence of HIPK2-mediated transcriptional regulation of HIF-1alpha that might play a critical role in VEGF expression. ..
- Puca R, Nardinocchi L, Pistritto G, D Orazi G. Overexpression of HIPK2 circumvents the blockade of apoptosis in chemoresistant ovarian cancer cells. Gynecol Oncol. 2008;109:403-10 pubmed publisher..Exogenous HIPK2 might represent a novel therapeutic approach to circumvent inhibition of apoptosis in treatment of chemoresistant ovarian cancers with wtp53. ..
- Wee H, Voon D, Bae S, Ito Y. PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis. Blood. 2008;112:3777-87 pubmed publisher..Therefore, phosphorylation of RUNX1 appears a critical step in its association with and phosphorylation of p300, and its disruption may be a common theme in RUNX1-associated leukemogenesis. ..
- Nardinocchi L, Puca R, Sacchi A, D Orazi G. Inhibition of HIF-1alpha activity by homeodomain-interacting protein kinase-2 correlates with sensitization of chemoresistant cells to undergo apoptosis. Mol Cancer. 2009;8:1 pubmed publisher..Thus potential use of HIPK2 is promising for cancer treatment by potentiating cytotoxic therapies, regardless of p53 cell status. ..
- Di Stefano V, Mattiussi M, Sacchi A, D Orazi G. HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations. FEBS Lett. 2005;579:5473-80 pubmed
- Sung K, Lee Y, Kim E, Lee S, Ahn J, Choi C. Role of the SUMO-interacting motif in HIPK2 targeting to the PML nuclear bodies and regulation of p53. Exp Cell Res. 2011;317:1060-70 pubmed publisher..These results suggest that SIM-mediated HIPK2 targeting to PML-NBs is crucial for HIPK2-mediated p53 activation and induction of apoptosis. ..
- D Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S, et al. Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nat Cell Biol. 2002;4:11-9 pubmed..These data define a new functional interaction between p53 and HIPK2 that results in the targeted subcellular localization of p53 and initiation of apoptosis. ..
- Choi D, Na W, Kabir M, Yi E, Kwon S, Yeom J, et al. WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation. Mol Cell. 2013;51:374-85 pubmed publisher..Taken together, HIPK2 plays a critical role in the initiation of DSB repair signaling by controlling WIP1 levels in response to IR. ..
- Cecchinelli B, Lavra L, Rinaldo C, Iacovelli S, Gurtner A, Gasbarri A, et al. Repression of the antiapoptotic molecule galectin-3 by homeodomain-interacting protein kinase 2-activated p53 is required for p53-induced apoptosis. Mol Cell Biol. 2006;26:4746-57 pubmed..Furthermore, expression of a nonrepressible Gal-3 prevents HIPK2- and p53-induced apoptosis. These results reveal a new apoptotic pathway induced by HIPK2-activated p53 and requiring repression of the antiapoptotic factor Gal-3. ..
- D Orazi G, Sciulli M, Di Stefano V, Riccioni S, Frattini M, Falcioni R, et al. Homeodomain-interacting protein kinase-2 restrains cytosolic phospholipase A2-dependent prostaglandin E2 generation in human colorectal cancer cells. Clin Cancer Res. 2006;12:735-41 pubmed..Our findings reveal the novel mechanism of HIPK2 to restrain progression of human colon tumorigenesis, at least in part, by turning off cPLA2-dependent PGE2 generation. ..
- Dauth I, Krüger J, Hofmann T. Homeodomain-interacting protein kinase 2 is the ionizing radiation-activated p53 serine 46 kinase and is regulated by ATM. Cancer Res. 2007;67:2274-9 pubmed..Taken together, our findings indicate that HIPK2 is the IR-activated p53 Ser(46) kinase and is regulated by ATM. ..
- Rinaldo C, Prodosmo A, Mancini F, Iacovelli S, Sacchi A, Moretti F, et al. MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis. Mol Cell. 2007;25:739-50 pubmed
- de La Vega L, Grishina I, Moreno R, Kruger M, Braun T, Schmitz M. A redox-regulated SUMO/acetylation switch of HIPK2 controls the survival threshold to oxidative stress. Mol Cell. 2012;46:472-83 pubmed publisher..Although a nonacetylatable HIPK2 mutant enhanced ROS-induced cell death, an acetylation-mimicking variant ensured cell survival even under conditions of high oxidative stress. ..
- Aikawa Y, Nguyen L, Isono K, Takakura N, Tagata Y, Schmitz M, et al. Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation. EMBO J. 2006;25:3955-65 pubmed..HIPK2 also phosphorylates another co-activator, MOZ, in an AML1-dependent manner. We discuss a possible mechanism by which transcription factors could regulate local histone acetylation and transcription of their target genes. ..
- Choi D, Seo Y, Kim E, Sung K, Ahn J, Park S, et al. Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by WD40 repeat/SOCS box protein WSB-1. J Biol Chem. 2008;283:4682-9 pubmed..These findings effectively illustrate the regulatory mechanisms by which HIPK2 is maintained at a low level, by WSB-1 in cells under normal conditions, and stabilized by genotoxic stresses. ..
- Kim Y, Choi C, Lee S, Conti M, Kim Y. Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors. J Biol Chem. 1998;273:25875-9 pubmed..Thus, HIPKs represent a heretofore undescribed family of co-repressors for homeodomain transcription factors. ..
- Puca R, Nardinocchi L, Gal H, Rechavi G, Amariglio N, Domany E, et al. Reversible dysfunction of wild-type p53 following homeodomain-interacting protein kinase-2 knockdown. Cancer Res. 2008;68:3707-14 pubmed publisher..These results show a critical role of HIPK2 in maintaining the transactivation activity of wtp53 and further suggest that low expression of HIPK2 may impair the p53 function in tumors harboring wtp53. ..
- Nardinocchi L, Puca R, D Orazi G. HIF-1? antagonizes p53-mediated apoptosis by triggering HIPK2 degradation. Aging (Albany NY). 2011;3:33-43 pubmed..Our findings identify a novel circuitry between HIF-1? and p53, and provide a paradigm for HIPK2 dictating cell response to antitumor therapies. ..
- Li X, Wang Y, Debatin K, Hug H. The serine/threonine kinase HIPK2 interacts with TRADD, but not with CD95 or TNF-R1 in 293T cells. Biochem Biophys Res Commun. 2000;277:513-7 pubmed..Under the conditions where HIPK2/TRADD association was found, no direct interaction of HIPK2 with CD95, TNF-R1, FADD or caspase-8 could be detected. Therefore, HIPK2 may play a role in TNF-R1 mediated signaling. ..
- Kim Y, Choi C, Kim Y. Covalent modification of the homeodomain-interacting protein kinase 2 (HIPK2) by the ubiquitin-like protein SUMO-1. Proc Natl Acad Sci U S A. 1999;96:12350-5 pubmed..Thus, our results provide firm evidence that the nuclear protein kinase HIPK2 can be covalently modified by SUMO-1, which directs its localization to nuclear speckles (dots). ..
- Rinaldo C, Moncada A, Gradi A, Ciuffini L, D Eliseo D, Siepi F, et al. HIPK2 controls cytokinesis and prevents tetraploidization by phosphorylating histone H2B at the midbody. Mol Cell. 2012;47:87-98 pubmed publisher..Overall, our data uncover mechanisms of a critical HIPK2 function in cytokinesis and in the prevention of tetraploidization. ..
- Nardinocchi L, Puca R, Givol D, D Orazi G. Counteracting MDM2-induced HIPK2 downregulation restores HIPK2/p53 apoptotic signaling in cancer cells. FEBS Lett. 2010;584:4253-8 pubmed publisher..These results suggest that zinc derivatives are potential molecules to target the MDM2-induced HIPK2/p53 inhibition. ..
- Gresko E, Möller A, Roscic A, Schmitz M. Covalent modification of human homeodomain interacting protein kinase 2 by SUMO-1 at lysine 25 affects its stability. Biochem Biophys Res Commun. 2005;329:1293-9 pubmed..The N-terminal SUMO-1 modification site is conserved between all vertebrate HIPK2 proteins and is found in all members of the HIPK family of protein kinases. Accordingly, also human HIPK3 is modified by sumoylation. ..
- Calzado M, de La Vega L, Möller A, Bowtell D, Schmitz M. An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response. Nat Cell Biol. 2009;11:85-91 pubmed publisher..As HIPK2 has an important role as a negative regulator of gene expression, its elimination from promoter-associated repressor complexes allows the induction of a substantial fraction of hypoxia-induced genes. ..
- Pierantoni G, Bulfone A, Pentimalli F, Fedele M, Iuliano R, Santoro M, et al. The homeodomain-interacting protein kinase 2 gene is expressed late in embryogenesis and preferentially in retina, muscle, and neural tissues. Biochem Biophys Res Commun. 2002;290:942-7 pubmed..Conversely, HIPK2 is ubiquitously expressed in murine and human adult tissues. We have also found that HIPK2 expression is reduced in breast and thyroid carcinomas, suggesting a role of this gene in the process of carcinogenesis. ..
- Puca R, Nardinocchi L, D Orazi G. Regulation of vascular endothelial growth factor expression by homeodomain-interacting protein kinase-2. J Exp Clin Cancer Res. 2008;27:22 pubmed publisher..These findings support the function of HIPK2 as tumor suppressor and hypothesise a role for HIPK2 as antiangiogenic tool in tumor therapy approaches. ..
- Pierantoni G, Fedele M, Pentimalli F, Benvenuto G, Pero R, Viglietto G, et al. High mobility group I (Y) proteins bind HIPK2, a serine-threonine kinase protein which inhibits cell growth. Oncogene. 2001;20:6132-41 pubmed..Since normal thyroid cells do not express detectable HMGI(Y) protein levels, we assume that the HIPK2 inhibitory effect is independent from the interaction with the HMGI(Y) protein. ..
- Di Stefano V, Blandino G, Sacchi A, Soddu S, D Orazi G. HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function. Oncogene. 2004;23:5185-92 pubmed..These results shed new light on the mechanisms by which the HIPK2/p53 pathway promotes apoptosis and suppression of tumorigenesis. ..
- Muschik D, Braspenning Wesch I, Stockfleth E, Rösl F, Hofmann T, Nindl I. Cutaneous HPV23 E6 prevents p53 phosphorylation through interaction with HIPK2. PLoS ONE. 2011;6:e27655 pubmed publisher..Thus, cutaneous HPV23 E6 prevents HIPK2-mediated p53 Ser 46 phosphorylation, which may favour survival of UV-damaged keratinocytes and skin carcinogenesis by apoptosis evasion. ..
- Hikasa H, Sokol S. Phosphorylation of TCF proteins by homeodomain-interacting protein kinase 2. J Biol Chem. 2011;286:12093-100 pubmed publisher..These observations emphasize a critical role for Wnt/HIPK2-dependent TCF phosphorylation and suggest that TCF switching is an important mechanism of Wnt target gene activation in vertebrate embryos...
- Choi C, Kim Y, Kwon H, Kim Y. The homeodomain protein NK-3 recruits Groucho and a histone deacetylase complex to repress transcription. J Biol Chem. 1999;274:33194-7 pubmed..NK-3 homeodomain protein is a transcriptional repressor that recruits the nuclear protein kinase, homeodomain interacting protein kinase 2 (HIPK2)...
- Li X, Arai Y, Harada H, Shima Y, Yoshida H, Rokudai S, et al. Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1- and p53-mediated transcription. Oncogene. 2007;26:7231-9 pubmed..The mutants showed decreased activities and a dominant-negative function over wild-type protein in AML1- and p53-dependent transcription. These findings suggest that dysfunction of HIPK2 may play a role in the pathogenesis of leukemia. ..
- Pistritto G, Puca R, Nardinocchi L, Sacchi A, D Orazi G. HIPK2-induced p53Ser46 phosphorylation activates the KILLER/DR5-mediated caspase-8 extrinsic apoptotic pathway. Cell Death Differ. 2007;14:1837-9 pubmed
- Bitomsky N, Conrad E, Moritz C, Polonio Vallon T, Sombroek D, Schultheiss K, et al. Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. Proc Natl Acad Sci U S A. 2013;110:E4203-12 pubmed publisher..Our results identify an evolutionary conserved mechanism regulating DNA damage-induced apoptosis...
- Yu J, Deshmukh H, Gutmann R, Emnett R, Rodriguez F, Watson M, et al. Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology. 2009;73:1526-31 pubmed publisher..The purpose of this study was to further investigate the frequency of BRAF and HIPK2 alterations in PAs, the concordance of these events, and their relationship to clinical phenotype...
- McDonough H, Charles P, Hilliard E, Qian S, Min J, Portbury A, et al. Stress-dependent Daxx-CHIP interaction suppresses the p53 apoptotic program. J Biol Chem. 2009;284:20649-59 pubmed publisher..By abrogating p53-dependent apoptotic pathways and by ubiquitination competitive with Daxx sumoylation, CHIP integrates the proteotoxic stress response of the cell with cell cycle pathways that influence cell survival. ..
- De Nicola F, Catena V, Rinaldo C, Bruno T, Iezzi S, Sorino C, et al. HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation. Cell Death Dis. 2014;5:e1414 pubmed publisher..Notably, Che-1 overexpression strongly counteracts HIPK2-induced apoptosis. Our results establish Che-1 as a new HIPK2 target and confirm its important role in the cellular response to DNA damage. ..
- Wang G, Zhu L, Zhao Y, Gao S, Sun D, Yuan J, et al. A natural product from Cannabis sativa subsp. sativa inhibits homeodomain-interacting protein kinase 2 (HIPK2), attenuating MPP+-induced apoptosis in human neuroblastoma SH-SY5Y cells. Bioorg Chem. 2017;72:64-73 pubmed publisher..In conclusion, these findings discovered a natural product that inhibited HIPK2, and highlighted that ZMHC could be a potential precursor agent for future PD therapy. ..
- Möller A, Schmitz M. Viruses as hijackers of PML nuclear bodies. Arch Immunol Ther Exp (Warsz). 2003;51:295-300 pubmed..Here we feature the different viral strategies leading to the hijacking of PML-NBs and discuss the consequences for the immune response. ..
- de La Vega L, Fröbius K, Moreno R, Calzado M, Geng H, Schmitz M. Control of nuclear HIPK2 localization and function by a SUMO interaction motif. Biochim Biophys Acta. 2011;1813:283-97 pubmed publisher..HIPK2 mutants with an inactive SIM showed changed activities, thus revealing that non-covalent binding of SUMO to the kinase is important for the regulation of its function. ..
- Calzado M, de La Vega L, Munoz E, Schmitz M. Autoregulatory control of the p53 response by Siah-1L-mediated HIPK2 degradation. Biol Chem. 2009;390:1079-83 pubmed publisher..The stimulating effect of HIPK2 on p53-triggered transcription is counteracted by Siah-1L, thus showing the occurrence of another negative feedback loop controlling the p53 response. ..
- Ciarapica R, Methot L, Tang Y, Lo R, Dali R, Buscarlet M, et al. Prolyl isomerase Pin1 and protein kinase HIPK2 cooperate to promote cortical neurogenesis by suppressing Groucho/TLE:Hes1-mediated inhibition of neuronal differentiation. Cell Death Differ. 2014;21:321-32 pubmed publisher..These results provide evidence that HIPK2 and Pin1 work together to promote cortical neurogenesis, at least in part, by suppressing Gro/TLE1:Hes1-mediated inhibition of neuronal differentiation. ..
- Möller A, Sirma H, Hofmann T, Staege H, Gresko E, Lüdi K, et al. Sp100 is important for the stimulatory effect of homeodomain-interacting protein kinase-2 on p53-dependent gene expression. Oncogene. 2003;22:8731-7 pubmed..In summary, these experiments reveal a novel function for Sp100 as a coactivator for HIPK2-mediated p53 activation. ..