HIPK2
Identifiers
AliasesHIPK2, PRO0593, homeodomain interacting protein kinase 2
External IDsOMIM: 606868 MGI: 1314872 HomoloGene: 68766 GeneCards: HIPK2
Orthologs
SpeciesHumanMouse
Entrez

28996

15258

Ensembl

ENSG00000064393

ENSMUSG00000061436

UniProt

Q9H2X6

Q9QZR5

RefSeq (mRNA)

NM_001113239
NM_022740

NM_001136065
NM_001294143
NM_001294144
NM_010433

RefSeq (protein)

NP_001106710
NP_073577

NP_001129537
NP_001281072
NP_001281073
NP_034563

Location (UCSC)Chr 7: 139.56 – 139.78 MbChr 6: 38.67 – 38.85 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Homeodomain-interacting protein kinase 2 is an enzyme that in humans is encoded by the HIPK2 gene.[5] HIPK2 can be categorized as a Serine/Threonine Protein kinase, specifically one that interacts with homeodomain transcription factors.[6] It belongs to a family of protein kinases known as the DYRK kinases.[7] Within this family HIPK2 belongs to a group of homeodomain-interacting protein kinases (HIPKs), including HIPK1 and HIPK3.[8] HIPK2 can be found in a wide variety of species and its functions in gene expression and apoptosis are regulated by several different mechanisms.

Discovery

HIPK2 was discovered concurrently with HIPKs 1 and 3 in 1998. The HIPKs were discovered during an experiment that tried to identify genes that when expressed, yielded products that interacted with transcription factors related to the NK homeodomain .[8] HIPKs were discovered using a technique called Two-hybrid screening.[8] Two-hybrid screening is in conjunction with cDNA cloning, in which embryonic mouse cDNA libraries were used with mouse homeoprotein Nkx-1.2 to find genes involved with homeodomain transcription factors.[8] The researchers found two clones that were similar in protein sequence, demonstrated a strong interaction with the homeoprotein, and an active site characteristic of protein kinases.[8] These characteristics led to the name "HIPK". In 2000, the location of the HIPK2 gene was discovered to be on the long arm of Chromosome 7 (human) in the human genome.[7] In mice, HIPK2 was discovered to be on Chromosome 6.[7]

Homology

There is evidence to suggest that HIPKs including HIPK2 are evolutionarily conserved proteins across a wide array of species. The human sequence shares a close similarity to a sequence from the genome of Caenorhabditis elegans.[8] HIPKs also share a close similarity with YAK1 in yeast and are in the same family as a kinase from Dictyostelium.[7][8] Furthermore, HIPKs are able to interact with homeoproteins from other species, such as NK-1 and NK-3 in Drosophila as well as Nkx-2.5 in mice.[8] HIPK2 can also be found in dogs,[9] cats,[10] sheep,[11] and zebrafish[12] as well as many other species.

Localization

Expression in tissues

HIPK2 is expressed in nearly all tissue types, however it is highly expressed in the heart, muscle and kidneys.[13] HIPK2 has been shown to be expressed at the highest levels in the brain and neuronal tissues.[14] In addition to adult tissues, HIPK2 is also expressed late in the development of the Human embryo, specifically in the retina, muscles, and neural tissues.[14]

Sub-cellular localization

HIPK2 is found in the nucleus within structures called nuclear speckles.[7][15] It is also associated with PML bodies, which are also structures found in the nucleus.[16] Despite being found predominately in the nucleus, HIPK2 can also be Cytoplasmic.[17]

Structure

Gene

The HIPK2 gene contains 13 exons and 13 introns within the entire 59.1 Kilo-base pair sequence.[18][19] Along with the other HIPKs, it contains three conserved sequences: a protein kinase domain, an interaction domain, a PEST sequence, and a YH domain.[8] Alternative splicing produces three different messenger RNAs, which subsequently lead to the production of three Protein isoforms.[20]

Protein

The HIPK2 protein is 1198 amino acids in length and has a molecular weight of 130.97 kilodaltons.[21][22] The most abundant amino acids in the protein are serine, threonine and alanine, which make up approximately 30 percent of the proteins total amino acid count.[21] The structure of the protein in its native form is unstable.[21] The protein is made up of several regions which directly relate to its function, regulation, and localization. The protein kinase domain is 330 amino acids long and is located near the N-terminus of the protein.[23][24] In addition to its kinase domain, HIPK2 has two nuclear localization signals,[25] a SUMO interaction motif,[25] an auto-inhibitory domain[23] a transcriptional co-repression domain,[13] and several interaction domains, including one for p53.[26] While there are signals targeting HIPK2 to nuclear speckles, there is also a speckle retention sequence that causes HIPK2 to remain in the nuclear speckles.[17] The auto-inhibitory domain, which contains an ubiquitylation site at the K1182 residue is located at the C-terminus.[24]

Function

HIPK2 has two major functions. It acts as a co-repressor for NK homeodomain transcription factors, increasing their DNA binding affinity and their repressive effect on transcription.[8] HIPK2 participates in the regulation of gene expression through its contribution to regulating homeobox genes. These genes encode transcription factors that act to regulate target genes.[8] HIPK2 also acts in signal transduction, specifically the pathway leading to programmed cell death (apoptosis). HIPK2 can promote apoptosis either in association with p53 or by a separate mechanism. HIPK2 phosphorylates the S46 residue of p53, leading to its activation, which in turn leads to the transcription of factors that induce apoptosis.[27] Phosphorylation of p53 by HIPK2 prevents the association of negative regulator Mdm2 to p53 and is necessary for the acetylation of the K382 residue in p53, which also serves as a functionally important modification.[27] Proper folding of p53 is essential for p53 function. The folding of p53 depends on the presence of zinc, and HIPK2 plays a role in zinc regulation.[28] Consequently, the absence of HIPK2 leads to p53 misfolding.[27] HIPK2 indirectly enhances p53 activity by phosphorylating negative regulators of p53, such as CtBP1 and Mdm2, leading to their degradation by the proteasome.[27][29] HIPK2 also has the ability to regulate cellular response to reactive oxygen species by regulating the expression of both oxidant and antioxidant genes.[30]

Regulation

HIPK2 is regulated by other proteins, as well as cellular conditions and post-translational modifications.[31][30][32][33]

Positive

Under conditions of DNA damage, HIPK2 is stabilized and subject to positive regulation. The activity of HIPK2 is increased through the action of caspase 6.[17] Caspase 6 cleaves HIPK2 at residue D916 and D977.[17] As a result, the auto-inhibitory domain is removed and the activity of HIPK2 increases. HIPK2 activity can also be increased through the action of checkpoint kinases. These kinases phosphorylate HIPK2 associated ubiquitin ligases and prevent their binding to HIPK2. As a result, the degradation of HIPK2 through the ubiquitin proteasome pathway is inhibited.[17][31] In conditions of oxidative stress, sumoylation of HIPK2 prevents acetylation, and as a result maintains its function in facilitating apoptosis.[30] Under normal physiological conditions however, acetylation of HIPK2 by a protein called p300 again stabilizes HIPK2 but, increases its ability to induce apoptosis.[32] Phosphorylation of HIPK2 at residues T880 and S882, via another kinase or through auto-phosphorylation, leads to the recruitment of PIN1 and stabilization of HIPK2.[33] This results in increased apoptotic function of HIPK2.[33]

Negative

Under regular conditions HIPK2 is unstable and is subject to negative regulation. HIPK2 is subject to regulation by the ubiquitin proteasome pathway, in which ubiquitin ligases bind to HIPK2, leading to polyubiquitination at the K1182 residue, localization to the proteasome and subsequent degradation of the protein. leads to protein degradation.[17][31] The PEST sequence found in HIPK2 is also linked to protein degradation.[34] HIPK2 activity can also be down regulated by the protein HMGA1, which transports it back to the cytoplasm.[17] In conditions of oxidative stress sumoylation of HIPK2 is discouraged and acetylation is promoted, resulting in its stabilization and the inhibition of its ability to facilitate apoptosis.[30]

p53

p53 regulates HIPK2 using both positive and negative mechanisms.[17] p53 binds to the third intron of the caspase 6 gene, and promotes the activation of the gene.[35] Caspase 6 in turn activates HIPK2. Conversely, p53 down regulates HIPK2 by activating the ubiquitin ligase mdm2. An interaction of mdm2 and HIPK2 leads to the ubiquitination and eventual degradation of HIPK2.[17]

Mutations

Two mutations have been discovered in the speckle retention sequence, both of which are missense.[36] One of which was named R868W, meaning that at residue 868 where the wild type amino acid sequence would have contained an arginine residue, it now contains a tryptophan residue. The other mutation was named N958I, meaning that at residue 958 where the wild type amino acid sequence would have contained an asparagine residue, it now contains an isoleucine residue. The R868W mutation is the result of cytosine to thymine point mutation and the N985I mutation resulted from an adenine to thymine point mutation.[36] The R868W mutation was found in exon 12 and the N985I mutation was found in exon 13.[36] These mutations lead to forms of HIPK2 that are less active and show abhorrent localization to nuclear speckles.[36] The speckle retention sequence is necessary for HIPK2 function in transcription activation as deletion of this sequence inhibits the function.[36]

Interactions

HIPK2 interacts with several other proteins:

Clinical significance

Improper HIPK2 function has been implicated in the pathology of diseases such as acute myeloid leukemia,[36] myelodysplastic syndrome[36] through mutations in the speckle retention sequence and Alzheimer's disease through hyperdegradation of HIPK2.[40] Consistent with its tissue expression patterns, loss of HIPK2 function has also been implicated in kidney fibrosis[41] and cardiovascular disease.[42]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000064393 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000061436 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Wang Y, Hofmann TG, Runkel L, Haaf T, Schaller H, Debatin K, Hug H (March 2001). "Isolation and characterization of cDNAs for the protein kinase HIPK2". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1518 (1–2): 168–72. doi:10.1016/S0167-4781(00)00308-0. PMID 11267674.
  6. ↑ Sung KS, Go YY, Ahn JH, Kim YH, Kim Y, Choi CY (June 2005). "Differential interactions of the homeodomain-interacting protein kinase 2 (HIPK2) by phosphorylation-dependent sumoylation". FEBS Letters. 579 (14): 3001–8. doi:10.1016/j.febslet.2005.04.053. PMID 15896780. S2CID 37551460.
  7. 1 2 3 4 5 Hofmann TG, Mincheva A, Lichter P, Dröge W, Schmitz ML (2000). "Human homeodomain-interacting protein kinase-2 (HIPK2) is a member of the DYRK family of protein kinases and maps to chromosome 7q32-q34". Biochimie. 82 (12): 1123–7. doi:10.1016/S0300-9084(00)01196-2. PMID 11120354.
  8. 1 2 3 4 5 6 7 8 9 10 11 12 Kim YH, Choi CY, Lee SJ, Conti MA, Kim Y (October 1998). "Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors". The Journal of Biological Chemistry. 273 (40): 25875–9. doi:10.1074/jbc.273.40.25875. PMID 9748262.
  9. ↑ "HIPK2 homeodomain interacting protein kinase 2 [Canis lupus familiaris (dog)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-29.
  10. ↑ "HIPK2 homeodomain interacting protein kinase 2 [Felis catus (domestic cat)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-29.
  11. ↑ "HIPK2 homeodomain interacting protein kinase 2 [Ovis aries (sheep)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-29.
  12. ↑ "hipk2 homeodomain interacting protein kinase 2 [Danio rerio (zebrafish)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-29.
  13. 1 2 Pierantoni GM, Bulfone A, Pentimalli F, Fedele M, Iuliano R, Santoro M, Chiariotti L, Ballabio A, Fusco A (January 2002). "The homeodomain-interacting protein kinase 2 gene is expressed late in embryogenesis and preferentially in retina, muscle, and neural tissues". Biochemical and Biophysical Research Communications. 290 (3): 942–7. doi:10.1006/bbrc.2001.6310. PMID 11798164.
  14. 1 2 Wang Y, Hofmann TG, Runkel L, Haaf T, Schaller H, Debatin K, Hug H (2001). "Isolation and characterization of cDNAs for the protein kinase HIPK2". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1518 (1–2): 168–72. doi:10.1016/S0167-4781(00)00308-0. PMID 11267674. The nucleotide sequence data have been deposited in GenBank under the accession numbers AF208291 and AF208292, respectively
  15. ↑ Kim YH, Choi CY, Kim Y (October 1999). "Covalent modification of the homeodomain-interacting protein kinase 2 (HIPK2) by the ubiquitin-like protein SUMO-1". Proceedings of the National Academy of Sciences of the United States of America. 96 (22): 12350–5. Bibcode:1999PNAS...9612350K. doi:10.1073/pnas.96.22.12350. PMC 22920. PMID 10535925.
  16. ↑ Sung KS, Lee YA, Kim ET, Lee SR, Ahn JH, Choi CY (April 2011). "Role of the SUMO-interacting motif in HIPK2 targeting to the PML nuclear bodies and regulation of p53". Experimental Cell Research. 317 (7): 1060–70. doi:10.1016/j.yexcr.2010.12.016. PMID 21192925.
  17. 1 2 3 4 5 6 7 8 9 10 11 12 13 Sombroek D, Hofmann TG (February 2009). "How cells switch HIPK2 on and off". Cell Death and Differentiation. 16 (2): 187–94. doi:10.1038/cdd.2008.154. PMID 18974774.
  18. ↑ Thierry-Mieg, Danielle; Thierry-Mieg, Jean. "AceView: Gene:HIPK2, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView". www.ncbi.nlm.nih.gov. Retrieved 2017-11-28.
  19. ↑ Zhang D, Li K, Erickson-Miller CL, Weiss M, Wojchowski DM (January 2005). "DYRK gene structure and erythroid-restricted features of DYRK3 gene expression". Genomics. 85 (1): 117–30. doi:10.1016/j.ygeno.2004.08.021. PMID 15607427.
  20. ↑ "HIPK2 - Homeodomain-interacting protein kinase 2 - Homo sapiens (Human) - HIPK2 gene & protein". www.uniprot.org. Retrieved 2017-11-28.
  21. 1 2 3 "ExPASy - ProtParam". web.expasy.org. Retrieved 2017-11-28.
  22. ↑ He Q, Shi J, Sun H, An J, Huang Y, Sheikh MS (2010). "Characterization of Human Homeodomain-interacting Protein Kinase 4 (HIPK4) as a Unique Member of the HIPK Family". Molecular and Cellular Pharmacology. 2 (2): 61–68. PMC 2876313. PMID 20508833.
  23. 1 2 Feng Y, Zhou L, Sun X, Li Q (March 2017). "Homeodomain-interacting protein kinase 2 (HIPK2): a promising target for anti-cancer therapies". Oncotarget. 8 (12): 20452–20461. doi:10.18632/oncotarget.14723. PMC 5386776. PMID 28107201.
  24. 1 2 Kuwano Y, Nishida K, Akaike Y, Kurokawa K, Nishikawa T, Masuda K, Rokutan K (September 2016). "Homeodomain-Interacting Protein Kinase-2: A Critical Regulator of the DNA Damage Response and the Epigenome". International Journal of Molecular Sciences. 17 (10): 1638. doi:10.3390/ijms17101638. PMC 5085671. PMID 27689990.
  25. 1 2 de la Vega L, Fröbius K, Moreno R, Calzado MA, Geng H, Schmitz ML (February 2011). "Control of nuclear HIPK2 localization and function by a SUMO interaction motif". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1813 (2): 283–97. doi:10.1016/j.bbamcr.2010.11.022. PMID 21145359.
  26. ↑ Kim EJ, Park JS, Um SJ (August 2002). "Identification and characterization of HIPK2 interacting with p73 and modulating functions of the p53 family in vivo". The Journal of Biological Chemistry. 277 (35): 32020–8. doi:10.1074/jbc.M200153200. PMID 11925430.
  27. 1 2 3 4 5 Puca R, Nardinocchi L, Givol D, D'Orazi G (August 2010). "Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells". Oncogene. 29 (31): 4378–87. doi:10.1038/onc.2010.183. PMID 20514025.
  28. ↑ Puca R, Nardinocchi L, Bossi G, Sacchi A, Rechavi G, Givol D, D'Orazi G (January 2009). "Restoring wtp53 activity in HIPK2 depleted MCF7 cells by modulating metallothionein and zinc". Experimental Cell Research. 315 (1): 67–75. doi:10.1016/j.yexcr.2008.10.018. PMID 18996371.
  29. 1 2 Zhang Q, Yoshimatsu Y, Hildebrand J, Frisch SM, Goodman RH (October 2003). "Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP". Cell. 115 (2): 177–86. doi:10.1016/S0092-8674(03)00802-X. PMID 14567915. S2CID 17430200.
  30. 1 2 3 4 de la Vega L, Grishina I, Moreno R, Krüger M, Braun T, Schmitz ML (May 2012). "A redox-regulated SUMO/acetylation switch of HIPK2 controls the survival threshold to oxidative stress". Molecular Cell. 46 (4): 472–83. doi:10.1016/j.molcel.2012.03.003. PMID 22503103.
  31. 1 2 3 Winter M, Sombroek D, Dauth I, Moehlenbrink J, Scheuermann K, Crone J, Hofmann TG (July 2008). "Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR". Nature Cell Biology. 10 (7): 812–24. doi:10.1038/ncb1743. PMID 18536714. S2CID 7668614.
  32. 1 2 3 Choi JR, Lee SY, Shin KS, Choi CY, Kang SJ (November 2017). "p300-mediated acetylation increased the protein stability of HIPK2 and enhanced its tumor suppressor function". Scientific Reports. 7 (1): 16136. Bibcode:2017NatSR...716136C. doi:10.1038/s41598-017-16489-w. PMC 5701035. PMID 29170424.
  33. 1 2 3 4 Wook Choi D, Yong Choi C (2014-10-29). "HIPK2 modification code for cell death and survival". Molecular & Cellular Oncology. 1 (2): e955999. doi:10.1080/23723548.2014.955999. PMC 4905192. PMID 27308327.
  34. 1 2 Rinaldo C, Prodosmo A, Mancini F, Iacovelli S, Sacchi A, Moretti F, Soddu S (March 2007). "MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis". Molecular Cell. 25 (5): 739–50. doi:10.1016/j.molcel.2007.02.008. PMID 17349959.
  35. 1 2 MacLachlan TK, El-Deiry WS (July 2002). "Apoptotic threshold is lowered by p53 transactivation of caspase-6". Proceedings of the National Academy of Sciences of the United States of America. 99 (14): 9492–7. Bibcode:2002PNAS...99.9492M. doi:10.1073/pnas.132241599. PMC 123168. PMID 12089322.
  36. 1 2 3 4 5 6 7 Li XL, Arai Y, Harada H, Shima Y, Yoshida H, Rokudai S, Aikawa Y, Kimura A, Kitabayashi I (November 2007). "Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1- and p53-mediated transcription". Oncogene. 26 (51): 7231–9. doi:10.1038/sj.onc.1210523. PMID 17533375.
  37. ↑ Kovács KA, Steinmann M, Halfon O, Magistretti PJ, Cardinaux JR (November 2015). "Complex regulation of CREB-binding protein by homeodomain-interacting protein kinase 2" (PDF). Cellular Signalling. 27 (11): 2252–60. doi:10.1016/j.cellsig.2015.08.001. hdl:10754/594104. PMID 26247811.
  38. ↑ Harada J, Kokura K, Kanei-Ishii C, Nomura T, Khan MM, Kim Y, Ishii S (October 2003). "Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation". The Journal of Biological Chemistry. 278 (40): 38998–9005. doi:10.1074/jbc.M307112200. PMID 12874272.
  39. ↑ Tomasini R, Samir AA, Carrier A, Isnardon D, Cecchinelli B, Soddu S, Malissen B, Dagorn JC, Iovanna JL, Dusetti NJ (September 2003). "TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity". The Journal of Biological Chemistry. 278 (39): 37722–9. doi:10.1074/jbc.M301979200. PMID 12851404.
  40. ↑ Lanni C, Nardinocchi L, Puca R, Stanga S, Uberti D, Memo M, Govoni S, D'Orazi G, Racchi M (April 2010). "Homeodomain interacting protein kinase 2: a target for Alzheimer's beta amyloid leading to misfolded p53 and inappropriate cell survival". PLOS ONE. 5 (4): e10171. Bibcode:2010PLoSO...510171L. doi:10.1371/journal.pone.0010171. PMC 2854690. PMID 20418953.
  41. ↑ Fan Y, Wang N, Chuang P, He JC (November 2014). "Role of HIPK2 in kidney fibrosis". Kidney International Supplements. 4 (1): 97–101. doi:10.1038/kisup.2014.18. PMC 4536960. PMID 26312158.
  42. ↑ Guo Y, Sui J, Zhang Q, Barnett J, Force T, Lal H (2017-11-14). "Abstract 18728: Loss of Homeodomain-Interacting Protein Kinase 2 in Cardiomyocytes Leads to Cardiac Dysfunction". Circulation. 136 (Suppl 1): A18728. ISSN 0009-7322.

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