Evaluation of cancer dependence and druggability of PRP4 kinase using cellular, biochemical, and structural approaches
| Autor: | Shih Min A Huang, Werngard Czechtizky, Feng Liu, David P. Harper, Carlos Garcia-Echeverria, Marion Dorsch, Tahir Majid, Dietmar Hoffmann, Heike Arlt, Zhuyan Guo, Bailin Zhang, Hong Cheng, Larry R. McLean, Ingrid Mechin, Qiang Gao, Christoph Lengauer, Kimberly Haas, Jessica McManus, Nayantara Kothari, Anlai Wang, Xin Chen, Dmitri Wiederschain, Gejing Deng, Vinod Patel, Jennifer L. Rocnik |
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| Rok vydání: | 2013 |
| Předmět: |
Proteomics
Genomics and Proteomics Kinase Drug discovery Ribonucleoprotein U4-U6 Small Nuclear Druggability Cancer Cell Biology Computational biology Biology medicine.disease Biochemistry Neoplasm Proteins Protein kinase domain Structural biology Cell Line Tumor Neoplasms Cancer cell medicine Humans Molecular Biology Protein Kinase Inhibitors |
| Zdroj: | The Journal of biological chemistry. 288(42) |
| ISSN: | 1083-351X |
| Popis: | PRP4 kinase is known for its roles in regulating pre-mRNA splicing and beyond. Therefore, a wider spectrum of PRP4 kinase substrates could be expected. The role of PRP4 kinase in cancer is also yet to be fully elucidated. Attaining specific and potent PRP4 inhibitors would greatly facilitate the study of PRP4 biological function and its validation as a credible cancer target. In this report, we verified the requirement of enzymatic activity of PRP4 in regulating cancer cell growth and identified an array of potential novel substrates through orthogonal proteomics approaches. The ensuing effort in structural biology unveiled for the first time unique features of PRP4 kinase domain and its potential mode of interaction with a low molecular weight inhibitor. These results provide new and important information for further exploration of PRP4 kinase function in cancer. Background: Little is known about the cancer dependence and druggability of PRP4. Results: Significance of PRP4 catalytic activity is demonstrated, novel substrates are identified, and features of kinase domain structure are revealed. Conclusion: PRP4 is required for cancer cell survival, displays substrate specificity, and is amenable to pharmacological inhibition. Significance: Our results indicate that PRP4 is a potential drug target to pursue in cancer. |
| Databáze: | OpenAIRE |
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