AI Article Synopsis
- Aurora kinase A (AURKA) is essential for cell division during mitosis and its activity is regulated by various interactions with cofactors.
- Researchers identified a specific region in the cofactor CEP192 that directly interacts with AURKA, using quantitative binding studies and crystal structure analysis.
- Disrupting this interaction in cells leads to mitotic defects, emphasizing the unique regulatory role of CEP192 compared to other cofactors like TPX2 in different cellular locations.
Article Abstract
Aurora kinase A (AURKA) performs critical functions in mitosis. Thus, the activity and subcellular localization of AURKA are tightly regulated and depend on diverse factors including interactions with the multiple binding cofactors. How these different cofactors regulate AURKA to elicit different levels of activity at distinct subcellular locations and times is poorly understood. Here, we identified a conserved region of CEP192, the major cofactor of AURKA, that mediates the interaction with AURKA. Quantitative binding studies were performed to map the interactions of a conserved helix (Helix-1) within CEP192. The crystal structure of Helix-1 bound to AURKA revealed a distinct binding site that is different from other cofactor proteins such as TPX2. Inhibiting the interaction between Helix-1 and AURKA in cells led to the mitotic defects, demonstrating the importance of the interaction. Collectively, we revealed a structural basis for the CEP192-mediated AURKA regulation at the centrosome, which is distinct from TPX2-mediated regulation on the spindle microtubule.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10121170 | PMC |
| http://dx.doi.org/10.1126/sciadv.adf8582 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
AURKA/PLK1/CDC25C Axis as a Novel Therapeutic Target in INI1-Deficient Epithelioid Sarcoma.
Cancer Sci
January 2025
Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Effective therapeutic strategies for epithelioid sarcoma (EpS), a high-grade soft tissue sarcoma characterized by loss of integrase interactor 1 (INI1), have not yet been developed. The present study therefore investigated the association between INI1 loss and upregulation of the aurora kinase A (AURKA)/polo-like kinase 1 (PLK1)/cell division cycle 25C (CDC25C) axis, as well as the therapeutic relevance of this axis in EpS. Notably, our findings showed that the reintroduction of INI1 in VA-ES-BJ cells significantly reduced proliferation, mitigated tumorigenicity, and negatively regulated the expression of AURKA and its downstream effectors, as well as the activation of PLK1 and CDC25C.
View Article and Find Full Text PDFTargeting N-Myc in neuroblastoma with selective Aurora kinase A degraders.
Cell Chem Biol
January 2025
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:
The N-Myc transcription factor, encoded by MYCN, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels.
View Article and Find Full Text PDFCell-Active, Arginine-Targeting Irreversible Covalent Inhibitors for Non-Kinases and Kinases.
Angew Chem Int Ed Engl
January 2025
Sun Yat-sen University - Shenzhen Campus, School of Pharmaceutical Sciences (Shenzhen), CHINA.
Targeted covalent inhibitors (TCIs) play an essential role in the fields of kinase research and drug discovery. Most existing TCIs are however cysteine- or lysine-reactive, thus severely limiting their potential applications. New types of TCIs capable of covalently targeting other nucleophilic amino acids that are readily available in proteins are urgently needed.
View Article and Find Full Text PDFThe bioinformatics analysis and experimental validation of the carcinogenic role of EXO1 in lung adenocarcinoma.
Front Oncol
December 2024
Department of Pathology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Background: Exonuclease 1 (EXO1), a protein involved in mismatch repair and recombination processes, has been identified as a prognostic biomarker in lung adenocarcinoma (LUAD). Nevertheless, its role in LUAD progression remains elusive. This study seeks to elucidate the functional significance of EXO1 in LUAD and evaluate its potential as a therapeutic target.
View Article and Find Full Text PDFIn Silico Method for ssDNA Aptamer Binding with Aurora Kinase A Protein.
Methods Mol Biol
January 2025
Department of Biotechnology, College of Natural and Applied Science, Addis Ababa Science and Technology University, Addis Ababa, Ethiopia.
While traditional assay methods face challenges in detecting specific proteins, aptamers, known for their high specificity and affinity, are emerging as a valuable biomarker detection tool. Aurora kinase A (AURKA) plays a role in cell division and influences stem cell reprogramming. In this study, an in silico approach method was conducted for a random ssDNA aptamer sequence selection and its binding with AURKA.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!