Human Gene HIPK2 (uc003vvf.4) Description and Page Index
Description: Homo sapiens homeodomain interacting protein kinase 2 (HIPK2), transcript variant 1, mRNA. RefSeq Summary (NM_022740): This gene encodes a conserved serine/threonine kinase that is a member of the homeodomain-interacting protein kinase family. The encoded protein interacts with homeodomain transcription factors and many other transcription factors such as p53, and can function as both a corepressor and a coactivator depending on the transcription factor and its subcellular localization. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]. Transcript (Including UTRs) Position: hg19 chr7:139,246,316-139,477,693 Size: 231,378 Total Exon Count: 15 Strand: - Coding Region Position: hg19 chr7:139,257,673-139,477,422 Size: 219,750 Coding Exon Count: 15
ID:HIPK2_HUMAN DESCRIPTION: RecName: Full=Homeodomain-interacting protein kinase 2; Short=hHIPk2; EC=188.8.131.52; FUNCTION: 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 phoyphorylation- mediated subnuclear localization shifting of PDX1. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. SUBUNIT: Interacts with CREB1, SIAH1, WSB1, CBX4, TRADD, p53/TP53, TP73, TP63, CREBBP, DAXX, P53DINP1, SKI, SMAD1, SMAD2 and SMAD3, but not SMAD4. Interacts with ATF1, PML, RUNX1, EP300, NKX1-2, NKX2-5, SPN/CD43, UBE2I, HMGA1, CTBP1, AXIN1, NLK, MYB, POU4F1, POU4F2, POU4F3, UBE2I, UBL1 and ZBTB4. Probably part of a complex consisting of p53/TP53, HIPK2 and AXIN1. SUBCELLULAR LOCATION: Nucleus, PML body. Cytoplasm. Note=Concentrated in PML/POD/ND10 nuclear bodies. Small amounts are cytoplasmic. TISSUE SPECIFICITY: Highly expressed in heart, muscle and kidney. Weakly expressed in a ubiquitous way. Down-regulated in several thyroid and breast tumors. INDUCTION: Unstable in unstressed cells but stabilized upon DNA damage. Induced by UV irradiation and other genotoxic agents (adriamycin ADR, cisplatin CDDP, etoposide, IR, roscovitin), thus triggering p53/TP53 apoptotic response. Consitutively negatively regulated by SIAH1 and WSB1 through proteasomal degradation. This negative regulation is impaired upon genotoxic stress. Repressed upon hypoxia (often associated with tumors), through MDM2- (an E3 ubiquitin ligases) mediated proteasomal degradation, thus inactivating p53/TP53 apoptotic response. This hypoxia repression is reversed by zinc. The stabilization mediated by DNA damage requires the damage checkpoint kinases ATM and ATR. PTM: Phosphorylated on tyrosines (By similarity). Autophosphorylated. PTM: Sumoylated. When conjugated it is directed to nuclear speckles. Desumoylated by SENP1 (By similarity). Sumoylation on Lys-32 is promoted by the E3 SUMO-protein ligase CBX4. PTM: Ubiquitinated by FBXO3, WSB1 and SIAH1, leading to rapid proteasome-dependent degradation. The degradation mediated by FBXO3, but not ubiquitination, is prevented in the presence of PML. The degradation mediated by WSB1 and SIAH1 is reversibly reduced upon DNA damage. PTM: Cleaved at Asp-923 and Asp-984 by CASP6 in a p53/TP53- dependent manner. The cleaved form lacks the autoinhibitory C- terminal domain (AID), resulting in a hyperactive kinase, which potentiates p53/TP53 Ser-46 phosphorylation and subsequent activation of the cell death machinery. MISCELLANEOUS: Interesting targets for cancer therapy. HIPK2 deregulation would end up in a multifactorial response leading to tumor chemoresistance by affecting p53/TP53 activity on one hand and to angiogenesis and cell proliferation by affecting HIF1A activity on the other hand. May provide important insights in the process of tumor progression, and may also serve as the crucial point in the diagnostic and therapeutical aspects of cancer. Tumor treatment may potential be improved by zinc supplementation in combination with chemotherapy to address hypoxia (PubMed:20514025). SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. HIPK subfamily. SIMILARITY: Contains 1 protein kinase domain.
Genetic Association Studies of Complex Diseases and Disorders
Diabetes Mellitus, Type 2 Laura J Scott et al. Science (New York, N.Y.) 2007, A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants., Science (New York, N.Y.).
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00069 - Protein kinase domain PF06293 - Lipopolysaccharide kinase (Kdo/WaaP) family PF07714 - Protein tyrosine kinase
SCOP Domains: 56112 - Protein kinase-like (PK-like)
ModBase Predicted Comparative 3D Structure on Q9H2X6
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0001654 eye development GO:0001934 positive regulation of protein phosphorylation GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006366 transcription from RNA polymerase II promoter GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0006974 cellular response to DNA damage stimulus GO:0006978 DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator GO:0007179 transforming growth factor beta receptor signaling pathway GO:0007224 smoothened signaling pathway GO:0007628 adult walking behavior GO:0008284 positive regulation of cell proliferation GO:0008344 adult locomotory behavior GO:0009952 anterior/posterior pattern specification GO:0010842 retina layer formation GO:0016310 phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0018107 peptidyl-threonine phosphorylation GO:0019048 modulation by virus of host morphology or physiology GO:0030182 neuron differentiation GO:0030218 erythrocyte differentiation GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway GO:0030514 negative regulation of BMP signaling pathway GO:0030578 PML body organization GO:0032092 positive regulation of protein binding GO:0042771 intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator GO:0043388 positive regulation of DNA binding GO:0043524 negative regulation of neuron apoptotic process GO:0045766 positive regulation of angiogenesis GO:0045893 positive regulation of transcription, DNA-templated GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0046330 positive regulation of JNK cascade GO:0048596 embryonic camera-type eye morphogenesis GO:0050882 voluntary musculoskeletal movement GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity GO:0051726 regulation of cell cycle GO:0060059 embryonic retina morphogenesis in camera-type eye GO:0060235 lens induction in camera-type eye GO:0060395 SMAD protein signal transduction GO:0061072 iris morphogenesis GO:0071456 cellular response to hypoxia GO:0097193 intrinsic apoptotic signaling pathway GO:1901796 regulation of signal transduction by p53 class mediator GO:2000059 negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process