| IED ID | IndEnz0002016019 |
| Enzyme Type ID | protease016019 |
| Protein Name |
Homeodomain-interacting protein kinase 2 hHIPk2 EC 2.7.11.1 |
| Gene Name | HIPK2 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MAPVYEGMASHVQVFSPHTLQSSAFCSVKKLKIEPSSNWDMTGYGSHSKVYSQSKNIPLSQPATTTVSTSLPVPNPSLPYEQTIVFPGSTGHIVVTSASSTSVTGQVLGGPHNLMRRSTVSLLDTYQKCGLKRKSEEIENTSSVQIIEEHPPMIQNNASGATVATATTSTATSKNSGSNSEGDYQLVQHEVLCSMTNTYEVLEFLGRGTFGQVVKCWKRGTNEIVAIKILKNHPSYARQGQIEVSILARLSTESADDYNFVRAYECFQHKNHTCLVFEMLEQNLYDFLKQNKFSPLPLKYIRPVLQQVATALMKLKSLGLIHADLKPENIMLVDPSRQPYRVKVIDFGSASHVSKAVCSTYLQSRYYRAPEIILGLPFCEAIDMWSLGCVIAELFLGWPLYPGASEYDQIRYISQTQGLPAEYLLSAGTKTTRFFNRDTDSPYPLWRLKTPDDHEAETGIKSKEARKYIFNCLDDMAQVNMTTDLEGSDMLVEKADRREFIDLLKKMLTIDADKRITPIETLNHPFVTMTHLLDFPHSTHVKSCFQNMEICKRRVNMYDTVNQSKTPFITHVAPSTSTNLTMTFNNQLTTVHNQAPSSTSATISLANPEVSILNYPSTLYQPSAASMAAVAQRSMPLQTGTAQICARPDPFQQALIVCPPGFQGLQASPSKHAGYSVRMENAVPIVTQAPGAQPLQIQPGLLAQQAWPSGTQQILLPPAWQQLTGVATHTSVQHATVIPETMAGTQQLADWRNTHAHGSHYNPIMQQPALLTGHVTLPAAQPLNVGVAHVMRQQPTSTTSSRKSKQHQSSVRNVSTCEVSSSQAISSPQRSKRVKENTPPRCAMVHSSPACSTSVTCGWGDVASSTTRERQRQTIVIPDTPSPTVSVITISSDTDEEEEQKHAPTSTVSKQRKNVISCVTVHDSPYSDSSSNTSPYSVQQRAGHNNANAFDTKGSLENHCTGNPRTIIVPPLKTQASEVLVECDSLVPVNTSHHSSSYKSKSSSNVTSTSGHSSGSSSGAITYRQQRPGPHFQQQQPLNLSQAQQHITTDRTGSHRRQQAYITPTMAQAPYSFPHNSPSHGTVHPHLAAAAAAAHLPTQPHLYTYTAPAALGSTGTVAHLVASQGSARHTVQHTAYPASIVHQVPVSMGPRVLPSPTIHPSQYPAQFAHQTYISASPASTVYTGYPLSPAKVNQYPYI |
| Enzyme Length | 1198 |
| Uniprot Accession Number | Q9H2X6 |
| Absorption | |
| Active Site | ACT_SITE 324; /note=Proton acceptor; /evidence=ECO:0000305 |
| Activity Regulation | |
| Binding Site | BINDING 228; /note=ATP; /evidence=ECO:0000305 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CATALYTIC ACTIVITY: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; |
| DNA Binding | |
| EC Number | 2.7.11.1 |
| Enzyme Function | 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 phosphorylation-mediated subnuclear localization shifting of PDX1. Involved in the regulation of eye size, lens formation and retinal lamination during late embryogenesis. {ECO:0000269|PubMed:11740489, ECO:0000269|PubMed:11925430, ECO:0000269|PubMed:12851404, ECO:0000269|PubMed:12874272, ECO:0000269|PubMed:14678985, ECO:0000269|PubMed:17018294, ECO:0000269|PubMed:17960875, ECO:0000269|PubMed:18695000, ECO:0000269|PubMed:18809579, ECO:0000269|PubMed:19015637, ECO:0000269|PubMed:19046997, ECO:0000269|PubMed:19448668, ECO:0000269|PubMed:20307497, ECO:0000269|PubMed:20573984, ECO:0000269|PubMed:20637728, ECO:0000269|PubMed:20980392, ECO:0000269|PubMed:21192925, ECO:0000269|PubMed:22825850}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 205..213; /note=ATP; /evidence=ECO:0000305 |
| Features | Active site (1); Alternative sequence (4); Beta strand (10); Binding site (1); Chain (1); Compositional bias (1); Cross-link (5); Domain (1); Helix (18); Modified residue (21); Motif (2); Mutagenesis (11); Natural variant (2); Nucleotide binding (1); Region (15); Sequence conflict (12); Site (2); Turn (3) |
| Keywords | 3D-structure;ATP-binding;Alternative splicing;Apoptosis;Cytoplasm;DNA damage;Isopeptide bond;Kinase;Nucleotide-binding;Nucleus;Phosphoprotein;Reference proteome;Serine/threonine-protein kinase;Transcription;Transcription regulation;Transferase;Ubl conjugation |
| Interact With | P61962; Q09472; P51608; Q01196; Q9H3D4 |
| Induction | 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. Consistutively 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. {ECO:0000269|PubMed:11740489, ECO:0000269|PubMed:18536714, ECO:0000269|PubMed:18974774, ECO:0000269|PubMed:19714248, ECO:0000269|PubMed:20514025}. |
| Subcellular Location | SUBCELLULAR LOCATION: Nucleus, PML body {ECO:0000269|PubMed:27211601}. Cytoplasm. Note=Concentrated in PML/POD/ND10 nuclear bodies. Small amounts are cytoplasmic. |
| Modified Residue | MOD_RES 16; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 118; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 135; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 141; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 252; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 273; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 361; /note=Phosphotyrosine; by autocatalysis; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 441; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 482; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 517; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 566; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 634; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 668; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 687; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 815; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 827; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 934; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 992; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 1041; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 1155; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5; MOD_RES 1188; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q9QZR5 |
| Post Translational Modification | PTM: Autophosphorylation at Tyr-361 in the activation loop activates the kinase and promotes nuclear localization. {ECO:0000250}.; 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. {ECO:0000250, ECO:0000269|PubMed:16253240, ECO:0000269|PubMed:17018294, ECO:0000269|PubMed:21145359, ECO:0000269|PubMed:21192925}.; 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. {ECO:0000269|PubMed:18093972, ECO:0000269|PubMed:18536714, ECO:0000269|PubMed:18809579}.; 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. {ECO:0000269|PubMed:16601678}. |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (2) |
| Cross Reference PDB | 6P5S; 7NCF; |
| Mapped Pubmed ID | 10587520; 11511362; 11780126; 14667819; 14990717; 15082531; 15122315; 15708980; 15766567; 15896780; 15958389; 16212962; 16332960; 16343438; 16407227; 16467083; 16730941; 16738336; 16917507; 17245128; 17332358; 17349959; 17533375; 17627287; 18395248; 18408760; 18483253; 18644116; 18996371; 19043406; 19128456; 19225110; 19438900; 19549727; 19567674; 19668373; 19794125; 19820693; 19828042; 19950553; 20379614; 20418953; 20624637; 20711500; 20849851; 20936779; 20940704; 21057547; 21173028; 21248071; 21248371; 21285352; 21514416; 21569099; 21602882; 21932419; 21988832; 22110707; 22236966; 22395153; 22406746; 22503103; 22658722; 22689412; 23000554; 23144866; 23485397; 23540226; 23565059; 23703384; 23722549; 23809146; 24107646; 24145406; 24196445; 24211575; 24244371; 24270405; 24824041; 24829283; 24846322; 25151962; 25210797; 25313037; 25421593; 25552543; 25630557; 25711204; 25778922; 25820028; 25868975; 25944899; 25961923; 26102034; 26113041; 26247811; 26625198; 27307198; 27335110; 27787517; 27884605; 27890429; 27901482; 28060750; 28607924; 28653891; 28692050; 29277937; 29428801; 29563611; 29666324; 29793420; 30932257; 30936013; 31066587; 31284535; 31341017; 31915028; 32034309; 32093146; 32593231; 32641685; 33063904; 33091504; 33326746; 33636538; 33650652; 33786814; 33964939; 34133717; 34785661; 9584153; 9651244; |
| Motif | MOTIF 802..805; /note=Nuclear localization signal 1 (NLS1); MOTIF 832..835; /note=Nuclear localization signal 2 (NLS2) |
| Gene Encoded By | |
| Mass | 130,966 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:17989; RHEA:46608 |
| Cross Reference Brenda | 2.7.11.1; |