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homeodomain-interacting protein kinase 2; hHIPk2 (HIPK2)

Function: - serine/threonine protein kinase with role in a) transcription regulation b) p53/TP53-mediated cellular apoptosis c) regulation of the cell cycle - acts as a corepressor of several transcription factors, including a) SMAD1 b) POU4F1/Brn3a c) probably NK homeodomain transcription factors - phosphorylates PDX1, ATF1, PML, p53/TP53, CREB1, CTBP1, CBX4, RUNX1, EP300, CTNNB1, HMGA1 & ZBTB4 - inhibits cell growth & promotes apoptosis through the activation of p53/TP53 both at the transcription level & at the protein level (by phosphorylation & indirect acetylation) - phosphorylation of p53/TP53 may be mediated by a p53/TP53-HIPK2-AXIN1 complex - role 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 & subsequent proteasomal degradation of CTNNB1 & the antiapoptotic factor CTBP1 - in the Wnt/beta-catenin signaling pathway acts as an intermediate kinase between TAK1 & NLK to promote proteasomal degradation of MYB - phosphorylates CBX4 upon DNA damage & promotes its E3 SUMO-protein ligase activity - activates CREB1 & ATF1 transcription factors by phosphorylation in response to genotoxic stress - in response to DNA damage, stabilizes PML by phosphorylation - PML, HIPK2 & FBXO3 may act synergically to activate p53/TP53-dependent transactivation - promotes angiogenesis, & is involved in erythroid differentiation, especially during fetal liver erythropoiesis - phosphorylation of RUNX1 & 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 - role in regulation of eye size, lens formation & retinal lamination during late embryogenesis - phosphorylated on Tyr (putative) - autophosphorylated - sumoylated - when conjugated, HIPK2 is directed to nuclear speckles - desumoylated by SENP1 (putative) - sumoylation on Lys-32 is promoted by the E3 SUMO-protein ligase CBX4 - ubiquitinated by FBXO3, WSB1 & SIAH1, leading to rapid proteasome-dependent degradation - degradation mediated by FBXO3, but not ubiquitination, is prevented in the presence of PML - degradation mediated by WSB1 & SIAH1 is reversibly reduced upon DNA damage - unstable in unstressed cells but stabilized upon DNA damage - cleaved at Asp-923 & Asp-984 by CASP6 (p53/TP53-dependent) - the cleaved form lacks the autoinhibitory C-terminal domain (AID), resulting in a hyperactive kinase, which potentiates p53/TP53 Ser-46 phosphorylation & subsequent activation of the cell death machinery - interacts with CREB1, SIAH1, WSB1, CBX4, TRADD, p53/TP53, TP73, TP63, CREBBP, DAXX, P53DINP1, SKI, SMAD1, SMAD2 & 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 & ZBTB4 - probably part of a complex consisting of p53/TP53, HIPK2 & AXIN1 Structure: - belongs to the protein kinase superfamily, CMGC Ser/Thr protein kinase family, HIPK subfamily - contains 1 protein kinase domain Compartment: - nucleus, PML body, cytoplasm - concentrated in PML/POD/ND10 nuclear bodies - small amounts are cytoplasmic Alternative splicing: named isoforms=3 Expression: - highly expressed in heart, muscle & kidney - weakly expression is ubiquitous - down-regulated in several thyroid & breast tumors - induced by UV irradiation & other genotoxic agents (adriamycin ADR, cisplatin CDDP, etoposide, IR, roscovitin), thus triggering p53/TP53 apoptotic response - constitutively negatively regulated by SIAH1 & WSB1 through proteasomal degradation - 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 - hypoxia repression is reversed by Zn+2 - stabilization mediated by DNA damage requires the damage checkpoint kinases ATM & ATR Notes: - ref [2] discusses HIPK2 & implications for cancer therapy

General

nuclear protein serine/threonine kinase

Properties

SIZE: entity length = 1198 aa MW = 131 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: Transcriptional corepression {97-230} DAXX interaction {189-520} kinase domain SITE: 199-527 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 205-213 ATP-binding site NAME: ATP-binding site SITE: 228-228 aspartate residue {D324} Tyr phosphorylation site {Y361} SKI/SMAD1 interaction {539-844} POU4F1 interaction {752-897} MOTIF: CTBP1 interaction {774-876} HMGA1 interaction {787-897} nuclear translocation signal {802-805} Ser phosphorylation site {S827} nuclear translocation signal {832-835} Thr phosphorylation site {T838} TP53/TP73 interaction {846-941} nuclear speckle localization {873-980} MOTIF: UBE2I interaction {873-907} SUMO interaction {884-908} proteolytic site {923-924} AXIN1 interaction {935-1049} Autoinhibitory domain (AID) {984-1198} MOTIF: proteolytic site {984-985} alanine-rich region {1088-1094} MOTIF: alanine residue (SEVERAL) STATE: active state

Database Correlations

OMIM 606868 UniProt Q9H2X6 Pfam PF00069 Entrez Gene 28996 Kegg hsa:28996 ENZYME 2.7.11.1

References

  1. UniProt :accession Q9H2X6
  2. Puca R et al Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells. Oncogene. 2010 Aug 5;29(31):4378-87. Epub 2010 May 31 PMID: 20514025