| Structural highlights
Function
[HIPK2_HUMAN] 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 phosphorylation-mediated subnuclear localization shifting of PDX1. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]
Publication Abstract from PubMed
The homeodomain-interacting protein kinase (HIPK) family is comprised of four nuclear protein kinases, HIPK1-4. HIPK proteins phosphorylate a diverse range of transcription factors involved in cell proliferation, differentiation and apoptosis. HIPK2, thus far the best characterized member of this largely understudied family of protein kinases, plays a role in the activation of p53 in response to DNA damage. Despite this tumor-suppressor function, HIPK2 is also found overexpressed in several cancers, and its hyperactivation causes chronic fibrosis. There are currently no structures of HIPK2 nor of any other HIPK kinase. Here, we report the crystal structure of HIPK2's kinase domain bound to CX-4945, a casein kinase 2a(CK2a) inhibitor currently in clinical trials against several cancers. The structure, determined at 2.2 A resolution, revealed that CX-4945 engages the HIPK2 active site in a hybrid binding mode between that seen in structures of CK2aand Pim1 kinases. The HIPK2 kinase domain crystallized in the active conformation, which was stabilized by phosphorylation of the activation loop. We noted that the overall kinase domain fold of HIPK2 closely resembles that of evolutionarily related dual-specificity tyrosine regulated kinases (DYRKs). Most significant structural differences between HIPK2 and DYRKs included an absence of the regulatory N-terminal domain, a unique conformation of the CMGC-insert region and of a newly defined insert segment in the aC-b4 loop. This first crystal structure of HIPK2 paves the way for characterizing the understudied members of the HIPK family and for developing HIPK2-directed therapies for managing cancer and fibrosis.
The crystal structure of the protein kinase HIPK2 reveals a unique architecture of its CMGC-insert region.,Agnew C, Liu L, Liu S, Xu W, You L, Yeung W, Kannan N, Jablons D, Jura N J Biol Chem. 2019 Jul 24. pii: RA119.009725. doi: 10.1074/jbc.RA119.009725. PMID:31341017[19]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Kim EJ, Park JS, Um SJ. Identification and characterization of HIPK2 interacting with p73 and modulating functions of the p53 family in vivo. J Biol Chem. 2002 Aug 30;277(35):32020-8. doi: 10.1074/jbc.M200153200. Epub 2002 , Mar 29. PMID:11925430 doi:http://dx.doi.org/10.1074/jbc.M200153200
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- ↑ Harada J, Kokura K, Kanei-Ishii C, Nomura T, Khan MM, Kim Y, Ishii S. Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation. J Biol Chem. 2003 Oct 3;278(40):38998-9005. Epub 2003 Jul 21. PMID:12874272 doi:http://dx.doi.org/10.1074/jbc.M307112200
- ↑ Hofmann TG, Stollberg N, Schmitz ML, 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 Dec 1;63(23):8271-7. PMID:14678985
- ↑ Roscic A, Moller A, Calzado MA, Renner F, Wimmer VC, Gresko E, Ludi KS, Schmitz ML. Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its substrate protein HIPK2. Mol Cell. 2006 Oct 6;24(1):77-89. PMID:17018294 doi:http://dx.doi.org/S1097-2765(06)00563-6
- ↑ Zhang Q, Wang Y. Homeodomain-interacting protein kinase-2 (HIPK2) phosphorylates HMGA1a at Ser-35, Thr-52, and Thr-77 and modulates its DNA binding affinity. J Proteome Res. 2007 Dec;6(12):4711-9. doi: 10.1021/pr700571d. Epub 2007 Oct 26. PMID:17960875 doi:http://dx.doi.org/10.1021/pr700571d
- ↑ Wee HJ, Voon DC, Bae SC, Ito Y. PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis. Blood. 2008 Nov 1;112(9):3777-87. doi: 10.1182/blood-2008-01-134122. Epub 2008, Aug 11. PMID:18695000 doi:http://dx.doi.org/10.1182/blood-2008-01-134122
- ↑ Shima Y, Shima T, Chiba T, Irimura T, Pandolfi PP, Kitabayashi I. PML activates transcription by protecting HIPK2 and p300 from SCFFbx3-mediated degradation. Mol Cell Biol. 2008 Dec;28(23):7126-38. doi: 10.1128/MCB.00897-08. Epub 2008 Sep , 22. PMID:18809579 doi:http://dx.doi.org/10.1128/MCB.00897-08
- ↑ Gresko E, Ritterhoff S, Sevilla-Perez J, Roscic A, Frobius K, Kotevic I, Vichalkovski A, Hess D, Hemmings BA, Schmitz ML. PML tumor suppressor is regulated by HIPK2-mediated phosphorylation in response to DNA damage. Oncogene. 2009 Feb 5;28(5):698-708. doi: 10.1038/onc.2008.420. Epub 2008 Nov 17. PMID:19015637 doi:http://dx.doi.org/10.1038/onc.2008.420
- ↑ Nardinocchi L, Puca R, Guidolin D, Belloni AS, Bossi G, Michiels C, Sacchi A, Onisto M, D'Orazi G. Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2 suggests a novel mechanism to restrain tumor growth. Biochim Biophys Acta. 2009 Feb;1793(2):368-77. doi: 10.1016/j.bbamcr.2008.10.013., Epub 2008 Nov 6. PMID:19046997 doi:http://dx.doi.org/10.1016/j.bbamcr.2008.10.013
- ↑ Yamada D, Perez-Torrado R, Filion G, Caly M, Jammart B, Devignot V, Sasai N, Ravassard P, Mallet J, Sastre-Garau X, Schmitz ML, Defossez PA. The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. Oncogene. 2009 Jul 9;28(27):2535-44. Epub 2009 May 18. PMID:19448668 doi:http://dx.doi.org/onc2009109
- ↑ Kim EA, Kim JE, Sung KS, Choi DW, Lee BJ, Choi CY. Homeodomain-interacting protein kinase 2 (HIPK2) targets beta-catenin for phosphorylation and proteasomal degradation. Biochem Biophys Res Commun. 2010 Apr 16;394(4):966-71. doi:, 10.1016/j.bbrc.2010.03.099. Epub 2010 Mar 20. PMID:20307497 doi:http://dx.doi.org/10.1016/j.bbrc.2010.03.099
- ↑ Sakamoto K, Huang BW, Iwasaki K, Hailemariam K, Ninomiya-Tsuji J, Tsuji Y. Regulation of genotoxic stress response by homeodomain-interacting protein kinase 2 through phosphorylation of cyclic AMP response element-binding protein at serine 271. Mol Biol Cell. 2010 Aug 15;21(16):2966-74. doi: 10.1091/mbc.E10-01-0015. Epub, 2010 Jun 23. PMID:20573984 doi:http://dx.doi.org/10.1091/mbc.E10-01-0015
- ↑ An R, da Silva Xavier G, Semplici F, Vakhshouri S, Hao HX, Rutter J, Pagano MA, Meggio F, Pinna LA, Rutter GA. Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is HIPK2-dependent and affects PDX1 subnuclear localization. Biochem Biophys Res Commun. 2010 Aug 20;399(2):155-61. doi:, 10.1016/j.bbrc.2010.07.035. Epub 2010 Jul 15. PMID:20637728 doi:http://dx.doi.org/10.1016/j.bbrc.2010.07.035
- ↑ Hailemariam K, Iwasaki K, Huang BW, Sakamoto K, Tsuji Y. Transcriptional regulation of ferritin and antioxidant genes by HIPK2 under genotoxic stress. J Cell Sci. 2010 Nov 15;123(Pt 22):3863-71. doi: 10.1242/jcs.073627. Epub 2010, Oct 27. PMID:20980392 doi:http://dx.doi.org/10.1242/jcs.073627
- ↑ Sung KS, Lee YA, Kim ET, Lee SR, Ahn JH, Choi CY. Role of the SUMO-interacting motif in HIPK2 targeting to the PML nuclear bodies and regulation of p53. Exp Cell Res. 2011 Apr 15;317(7):1060-70. doi: 10.1016/j.yexcr.2010.12.016. Epub , 2010 Dec 28. PMID:21192925 doi:http://dx.doi.org/10.1016/j.yexcr.2010.12.016
- ↑ Pelisch F, Pozzi B, Risso G, Munoz MJ, Srebrow A. DNA damage-induced heterogeneous nuclear ribonucleoprotein K sumoylation regulates p53 transcriptional activation. J Biol Chem. 2012 Aug 31;287(36):30789-99. doi: 10.1074/jbc.M112.390120. Epub, 2012 Jul 23. PMID:22825850 doi:http://dx.doi.org/10.1074/jbc.M112.390120
- ↑ Agnew C, Liu L, Liu S, Xu W, You L, Yeung W, Kannan N, Jablons D, Jura N. The crystal structure of the protein kinase HIPK2 reveals a unique architecture of its CMGC-insert region. J Biol Chem. 2019 Jul 24. pii: RA119.009725. doi: 10.1074/jbc.RA119.009725. PMID:31341017 doi:http://dx.doi.org/10.1074/jbc.RA119.009725
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