High-throughput kinase inhibitor screening reveals roles for Aurora and Nuak kinases in neurite initiation and dendritic branching

Sci Rep. 2021 Apr 14;11(1):8156. doi: 10.1038/s41598-021-87521-3.

Abstract

Kinases are essential regulators of a variety of cellular signaling processes, including neurite formation-a foundational step in neurodevelopment. Aberrant axonal sprouting and failed regeneration of injured axons are associated with conditions like traumatic injury, neurodegenerative disease, and seizures. Investigating the mechanisms underlying neurite formation will allow for identification of potential therapeutics. We used a kinase inhibitor library to screen 493 kinase inhibitors and observed that 45% impacted neuritogenesis in Neuro2a (N-2a) cells. Based on the screening, we further investigated the roles of Aurora kinases A, B, and C and Nuak kinases 1 and 2. The roles of Aurora and Nuak kinases have not been thoroughly studied in the nervous system. Inhibition or overexpression of Aurora and Nuak kinases in primary cortical neurons resulted in various neuromorphological defects, with Aurora A regulating neurite initiation, Aurora B and C regulating neurite initiation and elongation, all Aurora kinases regulating arborization, and all Nuak kinases regulating neurite initiation and elongation and arborization. Our high-throughput screening and analysis of Aurora and Nuak kinases revealed their functions and may contribute to the identification of therapeutics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aurora Kinase A / antagonists & inhibitors
  • Aurora Kinase A / genetics*
  • Aurora Kinase B / antagonists & inhibitors
  • Aurora Kinase B / genetics*
  • Cell Line
  • Female
  • High-Throughput Screening Assays
  • Loss of Function Mutation
  • Mice
  • Neurites / drug effects
  • Neurites / metabolism
  • Neurites / physiology*
  • Neurogenesis
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / genetics*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics*

Substances

  • Protein Kinase Inhibitors
  • Repressor Proteins
  • Protein Kinases
  • NUAK1 protein, mouse
  • Aurka protein, mouse
  • Aurkb protein, mouse
  • Aurora Kinase A
  • Aurora Kinase B
  • Protein Serine-Threonine Kinases
  • SNARK protein, mouse