HIPK2

HIPK2 is a conserved serine/threonine nuclear kinase that interacts with homeodomain transcription factors.[supplied by OMIM

Full Name

homeodomain interacting protein kinase 2

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.

Biological Process

Adult walking behavior Source: Ensembl
Anterior/posterior pattern specification Source: Ensembl
Cellular response to hypoxia Source: UniProtKB
DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator Source: BHF-UCL
Embryonic camera-type eye morphogenesis Source: Ensembl
Embryonic retina morphogenesis in camera-type eye Source: Ensembl
Erythrocyte differentiation Source: UniProtKB
Eye development Source: UniProtKB
Intrinsic apoptotic signaling pathway Source: UniProtKB
Intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator Source: GO_Central
Iris morphogenesis Source: Ensembl
Lens induction in camera-type eye Source: Ensembl
Negative regulation of BMP signaling pathway Source: UniProtKB
Negative regulation of neuron apoptotic process Source: Ensembl
Negative regulation of transcription by RNA polymerase II Source: Ensembl
Negative regulation of ubiquitin-dependent protein catabolic process Source: FlyBase
Neuron differentiation Source: Ensembl
Peptidyl-serine phosphorylation Source: BHF-UCL
Peptidyl-threonine phosphorylation Source: BHF-UCL
PML body organization Source: UniProtKB
Positive regulation of angiogenesis Source: UniProtKB
Positive regulation of cell population proliferation Source: Ensembl
Positive regulation of DNA binding Source: Ensembl
Positive regulation of DNA-binding transcription factor activity Source: BHF-UCL
Positive regulation of JNK cascade Source: UniProtKB
Positive regulation of protein binding Source: BHF-UCL
Positive regulation of protein phosphorylation Source: Ensembl
Positive regulation of transcription, DNA-templated Source: BHF-UCL
Positive regulation of transcription by RNA polymerase II Source: BHF-UCL
Positive regulation of transforming growth factor beta receptor signaling pathway Source: UniProtKB
Protein phosphorylation Source: UniProtKB
Regulation of cell cycle Source: UniProtKB
Regulation of signal transduction by p53 class mediator Source: Reactome
Retina layer formation Source: Ensembl
SMAD protein signal transduction Source: UniProtKB
Smoothened signaling pathway Source: GO_Central
Transforming growth factor beta receptor signaling pathway Source: Ensembl
Voluntary musculoskeletal movement Source: Ensembl

Cellular Location

Cytoplasm; PML body. Concentrated in PML/POD/ND10 nuclear bodies. Small amounts are cytoplasmic.

PTM

Autophosphorylation at Tyr-361 in the activation loop activates the kinase and promotes nuclear localization.
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.
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.
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.