HIPK2
Description
The HIPK2 (homeodomain interacting protein kinase 2) is a protein-coding gene located on chromosome 7.
Homeodomain-interacting protein kinase 2 (HIPK2) is an enzyme that in humans is encoded by the HIPK2 gene. HIPK2 can be categorized as a Serine/Threonine Protein kinase, specifically one that interacts with homeodomain transcription factors. It belongs to a family of protein kinases known as the DYRK kinases. Within this family HIPK2 belongs to a group of homeodomain-interacting protein kinases (HIPKs), including HIPK1 and HIPK3. HIPK2 can be found in a wide variety of species and its functions in gene expression and apoptosis are regulated by several different mechanisms.
== Discovery == HIPK2 was discovered concurrently with HIPKs 1 and 3 in 1998. The HIPKs were discovered during an experiment that tried to identify genes that when expressed, yielded products that interacted with transcription factors related to the NK homeodomain . HIPKs were discovered using a technique called Two-hybrid screening. Two-hybrid screening is in conjunction with cDNA cloning, in which embryonic mouse cDNA libraries were used with mouse homeoprotein Nkx-1.2 to find genes involved with homeodomain transcription factors. The researchers found two clones that were similar in protein sequence, demonstrated a strong interaction with the homeoprotein, and an active site characteristic of protein kinases.
HIPK2 (Homeodomain-interacting protein kinase 2) is a serine/threonine-protein kinase that plays a crucial role in regulating gene expression, cellular apoptosis, and the cell cycle. It acts as a corepressor for various transcription factors, including SMAD1, POU4F1/Brn3a, and likely NK homeodomain transcription factors. HIPK2 is known to phosphorylate a wide range of proteins, including PDX1, ATF1, PML, p53/TP53, CREB1, CTBP1, CBX4, RUNX1, EP300, CTNNB1, HMGA1, ZBTB4, and DAZAP2. This phosphorylation activity contributes to its diverse functions. HIPK2 is a key player in inhibiting cell growth and promoting apoptosis by activating p53/TP53 through both transcriptional and protein-level mechanisms. This activation involves phosphorylation and indirect acetylation of p53/TP53, often mediated by a complex containing p53/TP53, HIPK2, and AXIN1. HIPK2 also participates in the cellular response to hypoxia by acting as a transcriptional co-suppressor of HIF1A. Moreover, it mediates the transcriptional activation of TP73. In response to transforming growth factor beta (TGF-β), HIPK2 collaborates with DAXX to activate the JNK pathway. HIPK2 acts as a negative regulator by phosphorylating and promoting the proteasomal degradation of CTNNB1 and the antiapoptotic factor CTBP1. Within the Wnt/β-catenin signaling pathway, HIPK2 acts as an intermediate kinase between MAP3K7/TAK1 and NLK, facilitating the proteasomal degradation of MYB. Upon DNA damage, HIPK2 phosphorylates CBX4, enhancing its E3 SUMO-protein ligase activity. HIPK2 activates CREB1 and ATF1 transcription factors via phosphorylation in response to genotoxic stress. It also stabilizes PML by phosphorylation in response to DNA damage, and in conjunction with PML and FBXO3, it may synergistically activate p53/TP53-dependent transactivation. HIPK2 promotes angiogenesis and is involved in erythroid differentiation, particularly during fetal liver erythropoiesis. The phosphorylation of RUNX1 and EP300 by HIPK2 stimulates EP300's transcription regulation activity. In response to DNA damage, HIPK2 triggers ZBTB4 protein degradation. Additionally, HIPK2 phosphorylates DAZAP2, leading to its nuclear localization, decreased interaction with HIPK2, and prevention of DAZAP2-dependent ubiquitination of HIPK2 by E3 ubiquitin-protein ligase SIAH1, ultimately inhibiting proteasomal degradation. HIPK2 modulates the DNA-binding affinity of HMGA1. In response to high glucose, HIPK2 induces phosphorylation-mediated subnuclear localization shifting of PDX1. HIPK2 is involved in the regulation of eye size, lens formation, and retinal lamination during late embryogenesis. HIPK2 interacts with a range of proteins, including CREB1, SIAH1, WSB1, CBX4, TRADD, p53/TP53, TP73, TP63, CREBBP, DAXX, P53DINP1, SKI, SMAD1, SMAD2, and SMAD3, but not SMAD4. It also interacts with ATF1, PML, RUNX1, EP300, NKX1-2, NKX2-5, UBE2I, HMGA1, CTBP1, AXIN1, NLK, MYB, POU4F1, POU4F2, POU4F3, UBE2I, UBL1, and ZBTB4. HIPK2 is likely part of a complex consisting of p53/TP53, HIPK2, and AXIN1. It interacts with SP100, positively regulating TP53-dependent transcription. HIPK2 interacts with SUMO1P1/SUMO5, and its interaction with DAZAP2 leads to DAZAP2 phosphorylation, nuclear localization, reduced interaction with HIPK2, and prevention of DAZAP2-dependent degradation of HIPK2. The interaction between HIPK2 and SIAH1, promoted by DAZAP2, results in SIAH1-mediated ubiquitination and subsequent proteasomal degradation of HIPK2. In the context of microbial infection, HIPK2 interacts with both Hantaan and Seoul hantavirus nucleoproteins.
HIPK2 is also known as PRO0593.
