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Interrogation of kinase genetic interactions provides a global view of PAK1-mediated signal transduction pathways

Jae-Hong Kim1, Yeojin Seo1, Myungjin Jo1

  • 1Department of Pharmacology, Brain Science and Engineering Institute, and Department of Biomedical Sciences, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, South Korea.

The Journal of Biological Chemistry
|October 16, 2020
PubMed

Insights

This study identifies key genes regulating p21-activated kinase-1 (PAK1) in glioma, revealing new therapeutic targets. These findings highlight the importance of mitotic spindle, proteolysis, autophagy, and metabolism in cancer progression.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Kinases, including p21-activated kinase-1 (PAK1), are crucial in intracellular signaling and implicated in various cancers like glioma.
  • The complete signaling network associated with PAK1 remains incompletely defined.
  • Previous work established a yeast genetic interaction screen to identify candidate PAK1 interactions.

Purpose of the Study:

  • To define the signaling network of PAK1 in glioma.
  • To identify novel therapeutic targets for glioma treatment by examining PAK1 genetic interactions.

Main Methods:

  • A large-scale yeast genetic interaction screen was performed using toxicity as a readout.
  • 19 candidate PAK1 genetic interactions with human orthologs were selected and validated in mammalian cells, brain slice cultures, and orthotopic glioma models.
  • RNA interference (RNAi) and pharmacological inhibition were used to assess the function of candidate interactors.

Main Results:

  • Seven genes (DPP4, KIF11, mTOR, PKM2, SGPP1, TTK, YWHAE) were confirmed to regulate PAK1-induced glioma cell migration.
  • Genes involved in mitotic spindle, proteolysis, autophagy, and metabolism are critical for PAK1-mediated glioma cell migration, drug resistance, and proliferation.
  • AKT1 was identified as a downstream mediator of the PAK1-TTK genetic interaction.

Conclusions:

  • This study provides a comprehensive view of PAK1-mediated signal transduction pathways in glioma.
  • The identified genes and pathways represent potential novel therapeutic targets for glioma therapy.
Keywords:
PAK1cell migrationcell proliferationdrug resistancegenetic interactiongliomakinasemolecular cell biologysignal transduction

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