Last update 21 Mar 2024

HIPK2

homeodomain interacting protein kinase 2

Last update 21 Mar 2024

Basic Info

Synonyms

hHIPk2, HIPK2, homeodomain interacting protein kinase 2

+ [1]

Introduction

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, ZBTB4 and DAZAP2. 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. In response to DNA damage, phosphorylates DAZAP2 which localizes DAZAP2 to the nucleus, reduces interaction of DAZAP2 with HIPK2 and prevents DAZAP2-dependent ubiquitination of HIPK2 by E3 ubiquitin-protein ligase SIAH1 and subsequent proteasomal degradation (PubMed:33591310). 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.

100 Clinical Results associated with HIPK2

100 Translational Medicine associated with HIPK2

0 Patents (Medical) associated with HIPK2

495

Literatures (Medical) associated with HIPK2

08 Feb 2024·Human genomics

Gene expression analysis reveals diabetes-related gene signatures.

Article

Author: M I Farrim ; A Gomes ; D Milenkovic ; R Menezes

BACKGROUND:

Diabetes is a spectrum of metabolic diseases affecting millions of people worldwide. The loss of pancreatic β-cell mass by either autoimmune destruction or apoptosis, in type 1-diabetes (T1D) and type 2-diabetes (T2D), respectively, represents a pathophysiological process leading to insulin deficiency. Therefore, therapeutic strategies focusing on restoring β-cell mass and β-cell insulin secretory capacity may impact disease management. This study took advantage of powerful integrative bioinformatic tools to scrutinize publicly available diabetes-associated gene expression data to unveil novel potential molecular targets associated with β-cell dysfunction.

METHODS:

A comprehensive literature search for human studies on gene expression alterations in the pancreas associated with T1D and T2D was performed. A total of 6 studies were selected for data extraction and for bioinformatic analysis. Pathway enrichment analyses of differentially expressed genes (DEGs) were conducted, together with protein-protein interaction networks and the identification of potential transcription factors (TFs). For noncoding differentially expressed RNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which exert regulatory activities associated with diabetes, identifying target genes and pathways regulated by these RNAs is fundamental for establishing a robust regulatory network.

RESULTS:

Comparisons of DEGs among the 6 studies showed 59 genes in common among 4 or more studies. Besides alterations in mRNA, it was possible to identify differentially expressed miRNA and lncRNA. Among the top transcription factors (TFs), HIPK2, KLF5, STAT1 and STAT3 emerged as potential regulators of the altered gene expression. Integrated analysis of protein-coding genes, miRNAs, and lncRNAs pointed out several pathways involved in metabolism, cell signaling, the immune system, cell adhesion, and interactions. Interestingly, the GABAergic synapse pathway emerged as the only common pathway to all datasets.

CONCLUSIONS:

This study demonstrated the power of bioinformatics tools in scrutinizing publicly available gene expression data, thereby revealing potential therapeutic targets like the GABAergic synapse pathway, which holds promise in modulating α-cells transdifferentiation into β-cells.

09 Jan 2024·ACS omega

Circular RNA HIPK2 Promotes A1 Astrocyte Activation after Spinal Cord Injury through Autophagy and Endoplasmic Reticulum Stress by Modulating miR-124-3p-Mediated Smad2 Repression

Article

Author: Yang, Jin ; Dong, Junjie ; Li, Haotian ; Gong, Zhiqiang ; Wang, Bing ; Du, Kaili ; Zhang, Chunqiang ; Bi, Hangchuan ; Wang, Junfei ; Tian, Xinpeng ; Chen, Lingqiang

Glial scarring formed by reactive astrocytes after spinal cord injury (SCI) is the primary obstacle to neuronal regeneration within the central nervous system, making them a promising target for SCI treatment. Our previous studies have demonstrated the positive impact of miR-124-3p on neuronal repair, but it remains unclear how miR-124-3p is involved in autophagy or ER stress in astrocyte activation. To answer this question, the expression of A1 astrocyte-related markers at the transcriptional and protein levels after SCI was checked in RNA-sequencing data and verified using quantitative polymerase chain reaction (qPCR) and Western blotting in vitro and in vivo. The potential interactions among circHIPK2, miR-124-3p, and Smad2 were analyzed and confirmed by bioinformatics analyses and a luciferase reporter assay. In the end, the role of miR-124-3p in autophagy, ER stress, and SCI was investigated by using Western blotting to measure key biomarkers (C3, LC3, and Chop) in the absence or presence of corresponding selective inhibitors (siRNA, 4-PBA, TG). As a result, SCI caused the increase of A1 astrocyte markers, in which the upregulated circHIPK2 directly targeted miR-124-3p, and the direct downregulating effect of Smad2 by miR-124-3p was abolished, while Agomir-124 treatment reversed this effect. Injury caused a significant change of markers for ER stress and autophagy through the circHIPK2/miR-124-3p/Smad2 pathway, which might activate the A1 phenotype, and ER stress might promote autophagy in astrocytes. In conclusion, circHIPK2 may play a functional role in sequestering miR-124-3p and facilitating the activation of A1 astrocytes through regulating Smad2-mediated downstream autophagy and ER stress pathways, providing a new perspective on potential targets for functional recovery after SCI.

07 Jan 2024·Journal of cellular and molecular medicine

miR-664a-5p promotes experimental membranous nephropathy progression through HIPK2/Calpain1/GSα-mediated autophagy inhibition.

Article

Author: Zhiming Shan ; Zhenchao Zhuang ; Peiyao Ren ; Li Zhao ; Danna Zheng ; Wei Chen ; Juan Jin

We previously found that miR-664a-5p is specifically expressed in urinary exosomes of idiopathic membranous nephropathy (IMN) patients. Homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, plays an important role in nephropathy. But the function of these factors and their connection in MN are unclear. To investigate the function and mechanism of miR-664a-5p in MN, the miR-664a-5p expression in HK-2 cells, exosomes, podocytes and renal tissues were studied, as well as cell growth and apoptosis of these cells, the binding of miR-664a-5p to HIPK2 mRNA, the levels of relative proteins and autophagy. The MN progression in MN mice model was also studied. Albumin increased the miR-664a-5p content and apoptosis of HK-2 cells, which was blocked by miR-664a-5p antagomir. miR-664a-5p bound to the 3' UTR of HIPK2 mRNA, resulting in the up-regulation of Calpain1, GSα shear and the inhibition of autophagy level. Autophagy inhibitor CQ blocked the protective effect of miR-664a-5p antagomir, HIPK2 overexpression, Calpain inhibitor SJA6017 on albumin-mediated injury. MiR-664a-5p from albumin-treated HK-2 cells could be horizontally transported to podocytes through exosomes. Exosomes from albumin-treated HK-2 cells promoted progression of MN mice, AAV-Anti-miR-664-5p (mouse homology miRNA) could improve them. Albumin increases the miR-664a-5p level and causes changes of HIPK2/Calpain1/GSα pathway, which leads to autophagy inhibition and apoptosis up-regulation of renal tubular epithelial cells. miR-664a-5p can horizontally enter podocytes through exosomes resulting in podocytes injury. Targeted inhibition of miR-664a-5p can reduce the apoptosis of renal tubule cells and podocytes, and may improve the MN progression.

News (Medical) associated with HIPK2

09 Nov 2023

·www.biospace.com

Odyssey Therapeutics to Present Data for Three Immunology Programs at American College of Rheumatology Convergence 2023

BOSTON--(BUSINESS WIRE)-- Odyssey Therapeutics, Inc., a biotechnology company pioneering next-generation precision immunomodulators and oncology medicines, will present data highlighting three of its immunology programs at the American College of Rheumatology (ACR) Convergence 2023 meeting in San Diego, California, November 10-15, 2023. Odyssey’s oral and poster presentations will unveil the first public data for three novel therapeutic approaches to treat large populations with underserved inflammatory and autoimmune diseases. The receptor interacting protein kinase 2 (RIPK2) and interleukin-1 receptor-associated kinase 4 (IRAK4) scaffolding inhibitors, as well as tumor necrosis factor receptor-2 (TNFR2) agonist for regulatory T (Treg) cell modulation, represent targets and approaches of high interest in the pharmaceutical industry, given their broad potential to treat inflammatory disease. “Odyssey’s team of expert drug hunters are tirelessly working to pioneer groundbreaking therapeutic strategies for the management of autoimmune disease,” said Gary D. Glick, Ph.D., founder and CEO of Odyssey Therapeutics. “At ACR, we’ll give patients, researchers and investors the first look at our RIPK2 and IRAK4 scaffolding inhibitors, as well as TNFR2 agonist for Treg cell modulation. These therapies can offer transformative benefits for patients, and the findings shared at ACR reflect significant scientific progress and achievement by our team to understand and solve complex biology with small molecule and protein therapeutics.” Oral Presentation Title: Discovery of First-in-Class IRAK4 Scaffolding Inhibitors for the Treatment of Inflammatory Disorders Abstract number: 2505 Session type: Abstract Session Date and time: Tuesday, November 14, from 4-5:30 p.m. PST Poster Presentations Title: Discovery of a RIPK2 Scaffolding Inhibitor for the Treatment of Joint Autoimmune Diseases Abstract number: 0061 Session type: Poster Session A Date and time: Sunday, November 12, from 9-11 a.m. PST Title: Anti-TNFR2 VHH Agonistic Antibodies Promote and Stabilize Treg Immunosuppressive Activity Abstract number: 0068 Session type: Poster Session A Date and time: Sunday, November 12, from 9-11 a.m. PST About Odyssey Therapeutics Odyssey Therapeutics is a biotechnology company focused on discovering, developing and commercializing the next generation of immunomodulators and oncology medicines. Composed of an expert team of drug hunters, scientists and industry leaders in foundational biology, chemistry and data sciences, Odyssey is transforming drug discovery to accelerate and drive the creation and efficient delivery of life-enhancing precision medicines to patients. For more information, please visit odysseytx.com and follow Odyssey Therapeutics on X (formerly Twitter) and LinkedIn.

ImmunotherapyClinical StudyAACR

27 Oct 2022

·www.prnewswire.com

Rila Therapeutics Exits Stealth Mode

SAN FRANCISCO, Oct. 27, 2022 /PRNewswire/ -- Rila Therapeutics, a biotherapeutics company focused on addressing the critical unmet medical needs to treat renal fibrosis, today announced its emergence out of stealth mode. Rila Therapeutics has identified a promising, first-in-class allosteric small molecule targeting HIPK2 to inhibit kidney fibrosis. This breakthrough discovery aiming to advance the treatment of renal disease was developed in collaboration with Mount Sinai Innovation Partners and the Icahn School of Medicine at Mount Sinai (Icahn Mount Sinai), New York, NY. The company was founded by John He, MD, PhD, Chief of Nephrology at Icahn Mount Sinai and key opinion leader at one of the largest medical centers in the US, and ShangPharma Innovation. Dr. He, in addition to his position at Icahn Mount Sinai, is a professor of medicine and pharmacological sciences whose academic work has shed light on multiple features of kidney disease pathogenesis, leading to the elucidation of complex signaling networks in kidney cells by using systems biology approach and transgenic mouse models, and revealing the novel mechanisms of kidney fibrosis. He is also a member of the American Society of Clinical Investigation, American Association of Physicians, and former President of the Chinese American Society of Nephrology. "Currently, there are about 750,000 patients in the US suffering from renal fibrosis with no cure as there are no approved antifibrotic treatments targeting the kidney. Our goal is to drastically improve the lives of patients by increasing survival rates and decreasing the high costs of dialysis. I am excited for the potential of Rila to provide a safe and effective anti-fibrotic treatment," said Dr. He. The founding team also includes Kyung Lee, PhD, Associate Professor at Icahn Mount Sinai and NIH-funded principal investigator with over 12 years of research experience in nephrology; Robert Drakas, PhD, interim CEO of Rila Therapeutics and President of ShangPharma Innovation with 25+ years of pharmaceutical industry experience, and Michael Hui, Chairman of Rila Therapeutics, Managing Director and Co-Founder of Pandect Bioventures, and Chairman and CEO of ShangPharma Holdings. "I am thrilled Rila Therapeutics will be moving forward with IND enabling studies as this therapy is a novel first-in-class treatment for renal fibrosis," said Dr. Bob Drakas, CEO of Rila Therapeutics and President of ShangPharma Innovation. "We have a fantastic team of industry tenured innovators working to address the burden of chronic fibrotic disease for patients." Rila Therapeutics has secured patents to all background IP and composition of matter and will enter IND enabling studies in November 2022 with plans to submit IND to the FDA mid-year 2023. The small molecule targeting HIPK2 is based on technology developed by Mount Sinai faculty and licensed to Rila Therapeutics. Mount Sinai and Mount Sinai faculty, including Dr. He and Kyung (Kim) Lee have a financial interest in Rila Therapeutics. Mount Sinai also has representation on the Rila Therapeutics Board of Directors. About the Mount Sinai Health System The Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it. Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients' medical and emotional needs at the center of all treatment. About Rila Therapeutics Rila Therapeutics is a biotherapeutics company focused on addressing the critical unmet medical needs to treat renal fibrosis, founded between John He, MD, PhD Chief of Nephrology Mount Sinai Health System, Kyung Lee, PhD, Associate Professor at Icahn Mount Sinai, and ShangPharma Innovation with patents licensed through Mount Sinai Health System. Rila Therapeutics mission is to improve the lives of patients suffering from renal fibrosis by providing a safe and effective anti-fibrotic therapy. About ShangPharma Innovation Through strategic investments and partnerships, ShangPharma Innovation is focused on filling the critical investment gap that exists for earliest-stage therapeutic breakthroughs. Based in the San Francisco Bay Area, ShangPharma Innovation's experienced team of investors and scientists brings knowledge of diverse therapeutic areas, leverages multidimensional relationships across the spectrum of biotech and pharma to identify promising healthcare discoveries and work side-by-side with scientific innovators to rapidly advance ideas through key value-inflection points. ShangPharma Innovation embraces a founder-centric approach that ensures entrepreneurs can remain actively involved in shaping their company's successes, all with the proactive and trusted support of our wide network of experts. SOURCE Rila Therapeutics

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HIPK2

homeodomain interacting protein kinase 2

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