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Gene Review

HIPK2  -  homeodomain interacting protein kinase 2

Homo sapiens

Synonyms: Homeodomain-interacting protein kinase 2, hHIPk2
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Disease relevance of HIPK2


High impact information on HIPK2

  • Inducible phosphorylation of Pc2 at threonine 495 is required for its ability to increase HIPK2 sumoylation in response to DNA damage, thereby establishing an autoregulatory feedback loop between a SUMO substrate and its cognate E3 ligase [5].
  • DNA damage-induced HIPK2 directly phosphorylates Pc2 at multiple sites, which in turn controls Pc2 sumoylation and intranuclear localization [5].
  • The serine/threonine kinase HIPK2 phosphorylates the p53 protein at Ser 46, thus promoting p53-dependent gene expression and subsequent apoptosis [6].
  • 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 [6].
  • The resulting C-terminally truncated HIPK2 forms show an enhanced induction of the p53 response and cell death, thus allowing the rapid amplification of the p53-dependent apoptotic program during the initiation phase of apoptosis by a regulatory feed-forward loop [6].

Chemical compound and disease context of HIPK2


Biological context of HIPK2

  • Finally, we demonstrate that knockdown of endogenous HIPK2 using RNA interference inhibits TGF-beta-induced JNK activation and apoptosis [1].
  • A dominant negative form of HIPK2, in which the ATP binding motif in the kinase domain and the putative phosphorylation sites were mutated, enhanced Smad1/4-dependent transcription and the BMP-induced expression of alkaline phosphatase [7].
  • These results indicate that HIPK2, together with c-Ski, plays an important role in the negative regulation of BMP-induced transcriptional activation [7].
  • HIPK2 shows overlapping localization with p53 in promyelocytic leukemia (PML) nuclear bodies (PML-NBs) and functionally interacts with p53 to increase gene expression [8].
  • Downregulation of Sp100 levels by expression of siRNA does not interfere with p53-mediated transcription, but obviates the enhancing effect of HIPK2 [8].

Anatomical context of HIPK2


Associations of HIPK2 with chemical compounds


Physical interactions of HIPK2


Enzymatic interactions of HIPK2


Regulatory relationships of HIPK2

  • First, in wtp53-carrying cells HIPK2-dependent p53Ser46 phosphorylation selectively inhibits MDM2 at transcriptional level [14].
  • Here we demonstrate that HIPK2 regulates transforming growth factor (TGF) beta-induced c-Jun NH(2)-terminal kinase (JNK) activation and apoptosis [1].
  • HIPK2 efficiently inhibited Smad1/4-induced transcription from the Smad site-containing promoter [7].
  • Our previous studies indicate that HIPK2 participates in a pathway of UV-triggered CtBP clearance that results in cell death [18].
  • RESULTS AND CONCLUSIONS: We show here that HIPK2 activates transcription mediated by tumor suppressor p53 responsive promoter elements [12].
  • Concordantly, IR-induced HIPK2 accumulation is blocked by pharmacologic inhibition of ATM [20].
  • Hence, cytoplasmic relocalization of HIPK2 induced by HMGA1 overexpression is a mechanism of inactivation of p53 apoptotic function that we believe to be novel [21].

Other interactions of HIPK2


Analytical, diagnostic and therapeutic context of HIPK2


  1. 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. (2003) [Pubmed]
  2. US11 of herpes simplex virus type 1 interacts with HIPK2 and antagonizes HIPK2-induced cell growth arrest. Giraud, S., Diaz-Latoud, C., Hacot, S., Textoris, J., Bourette, R.P., Diaz, J.J. J. Virol. (2004) [Pubmed]
  3. 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. (2002) [Pubmed]
  4. Homeodomain-interacting protein kinase-2 restrains cytosolic phospholipase A2-dependent prostaglandin E2 generation in human colorectal cancer cells. D'Orazi, G., Sciulli, M.G., Di Stefano, V., Riccioni, S., Frattini, M., Falcioni, R., Bertario, L., Sacchi, A., Patrignani, P. Clin. Cancer Res. (2006) [Pubmed]
  5. Phosphorylation-Dependent Control of Pc2 SUMO E3 Ligase Activity by Its Substrate Protein HIPK2. Roscic, A., M??ller, A., Calzado, M.A., Renner, F., Wimmer, V.C., Gresko, E., L??di, K.S., Schmitz, M.L. Mol. Cell (2006) [Pubmed]
  6. 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. (2006) [Pubmed]
  7. 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. (2003) [Pubmed]
  8. Sp100 is important for the stimulatory effect of homeodomain-interacting protein kinase-2 on p53-dependent gene expression. Möller, A., Sirma, H., Hofmann, T.G., Staege, H., Gresko, E., Lüdi, K.S., Klimczak, E., Dröge, W., Will, H., Schmitz, M.L. Oncogene (2003) [Pubmed]
  9. Phosphorylation and transactivation of Pax6 by homeodomain-interacting protein kinase 2. Kim, E.A., Noh, Y.T., Ryu, M.J., Kim, H.T., Lee, S.E., Kim, C.H., Lee, C., Kim, Y.H., Choi, C.Y. J. Biol. Chem. (2006) [Pubmed]
  10. Inhibitory effects of homeodomain-interacting protein kinase 2 on the aorta-gonad-mesonephros hematopoiesis. Ohtsu, N., Nobuhisa, I., Mochita, M., Taga, T. Exp. Cell Res. (2007) [Pubmed]
  11. Covalent modification of human homeodomain interacting protein kinase 2 by SUMO-1 at lysine 25 affects its stability. Gresko, E., Möller, A., Roscic, A., Schmitz, M.L. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  12. HIPK2 overexpression leads to stabilization of p53 protein and increased p53 transcriptional activity by decreasing Mdm2 protein levels. Wang, Y., Debatin, K.M., Hug, H. BMC Mol. Biol. (2001) [Pubmed]
  13. 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. (2008) [Pubmed]
  14. HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations. Di Stefano, V., Mattiussi, M., Sacchi, A., D'Orazi, G. FEBS Lett. (2005) [Pubmed]
  15. FHL2 mediates p53-induced transcriptional activation through a direct association with HIPK2. Lee, S.W., Kim, E.J., Um, S.J. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  16. High mobility group I (Y) proteins bind HIPK2, a serine-threonine kinase protein which inhibits cell growth. Pierantoni, G.M., Fedele, M., Pentimalli, F., Benvenuto, G., Pero, R., Viglietto, G., Santoro, M., Chiariotti, L., Fusco, A. Oncogene (2001) [Pubmed]
  17. HIPK2 associates with RanBPM. Wang, Y., Marion Schneider, E., Li, X., Duttenhöfer, I., Debatin, K., Hug, H. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  18. Homeodomain-interacting protein kinase-2 mediates CtBP phosphorylation and degradation in UV-triggered apoptosis. Zhang, Q., Nottke, A., Goodman, R.H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  19. HIPK2 neutralizes MDM2 inhibition rescuing p53 transcriptional activity and apoptotic function. Di Stefano, V., Blandino, G., Sacchi, A., Soddu, S., D'Orazi, G. Oncogene (2004) [Pubmed]
  20. Homeodomain-interacting protein kinase 2 is the ionizing radiation-activated p53 serine 46 kinase and is regulated by ATM. Dauth, I., Krüger, J., Hofmann, T.G. Cancer Res. (2007) [Pubmed]
  21. High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2. Pierantoni, G.M., Rinaldo, C., Mottolese, M., Di Benedetto, A., Esposito, F., Soddu, S., Fusco, A. J. Clin. Invest. (2007) [Pubmed]
  22. 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. (2005) [Pubmed]
  23. 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. (2003) [Pubmed]
  24. 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. Möller, A., Sirma, H., Hofmann, T.G., Rueffer, S., Klimczak, E., Dröge, W., Will, H., Schmitz, M.L. Cancer Res. (2003) [Pubmed]
  25. 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) [Pubmed]
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