Subcellular drug targeting illuminates local kinase action

Paula J. Bucko, Chloe K. Lombard, Lindsay Rathbun, Irvin Garcia, Akansha Bhat, Linda Wordeman, F. Donelson Smith, Dustin J. Maly, Heidi Hehnly, John D. Scott

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Deciphering how signaling enzymes operate within discrete microenvironments is fundamental to understanding biological processes. A-kinase anchoring proteins (AKAPs) restrict the range of action of protein kinases within intracellular compartments. We exploited the AKAP targeting concept to create genetically encoded platforms that restrain kinase inhibitor drugs at distinct subcellular locations. Local Kinase Inhibition (LoKI) allows us to ascribe organelle-specific functions to broad specificity kinases. Using chemical genetics, super resolution microscopy, and live-cell imaging we discover that centrosomal delivery of Polo-like kinase 1 (Plk1) and Aurora A (AurA) inhibitors attenuates kinase activity, produces spindle defects, and prolongs mitosis. Targeted inhibition of Plk1 in zebrafish embryos illustrates how centrosomal Plk1 underlies mitotic spindle assembly. Inhibition of kinetochore-associated pools of AurA blocks phosphorylation of microtubule-kinetochore components. This versatile precision pharmacology tool enhances investigation of local kinase biology.

Original languageEnglish (US)
Article numbere52220
JournaleLife
Volume8
DOIs
StatePublished - Dec 2019

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Bucko, P. J., Lombard, C. K., Rathbun, L., Garcia, I., Bhat, A., Wordeman, L., Smith, F. D., Maly, D. J., Hehnly, H., & Scott, J. D. (2019). Subcellular drug targeting illuminates local kinase action. eLife, 8, [e52220]. https://doi.org/10.7554/eLife.52220