Small-molecule probe reveals a kinase cascade that links stress signaling to TCF/LEF and Wnt responsiveness

Cell Chem Biol. 2021 May 20;28(5):625-635.e5. doi: 10.1016/j.chembiol.2021.01.001. Epub 2021 Jan 26.

Abstract

Wnt signaling plays a central role in tissue maintenance and cancer. Wnt activates downstream genes through β-catenin, which interacts with TCF/LEF transcription factors. A major question is how this signaling is coordinated relative to tissue organization and renewal. We used a recently described class of small molecules that binds tubulin to reveal a molecular cascade linking stress signaling through ATM, HIPK2, and p53 to the regulation of TCF/LEF transcriptional activity. These data suggest a mechanism by which mitotic and genotoxic stress can indirectly modulate Wnt responsiveness to exert coherent control over cell shape and renewal. These findings have implications for understanding tissue morphogenesis and small-molecule anticancer therapeutics.

Keywords: Aurora kinases; LEF; TCF; Wnt; ataxia telangiectasia mutated/ATM; homeodomain-interacting protein kinase/HIPK2; p53; β-catenin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Humans
  • Male
  • Molecular Probes / chemistry
  • Molecular Probes / pharmacology*
  • Protein Serine-Threonine Kinases / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • TCF Transcription Factors / antagonists & inhibitors*
  • TCF Transcription Factors / genetics
  • TCF Transcription Factors / metabolism
  • Wnt Signaling Pathway / drug effects
  • Xenopus
  • Zebrafish
  • beta Catenin / antagonists & inhibitors*
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Molecular Probes
  • Small Molecule Libraries
  • TCF Transcription Factors
  • beta Catenin
  • Protein Serine-Threonine Kinases