homeodomain-interacting protein kinase 2; hHIPk2 (HIPK2)

Function

• serine/threonine protein kinase with role in
  • transcription regulation
  • p53/TP53-mediated cellular apoptosis
  • regulation of the cell cycle
• acts as a corepressor of several transcription factors, including
  • SMAD1
  • POU4F1/Brn3a
  • 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 discusses HIPK2 & implications for cancer therapy

More general terms

• serine/threonine kinase
• nuclear protein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=28996
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:28996
• OMIM: https://mirror.omim.org/entry/606868
• UniProt: http://www.uniprot.org/uniprot/Q9H2X6.html