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

Jiongjia Cheng; Masanao Tsuda; Karl Okolotowicz; Mary Dwyer; Paul J Bushway; Alexandre R Colas; Joseph J Lancman; Dennis Schade; Isaac Perea-Gil; Arne A N Bruyneel; Jaechol Lee; Nirmal Vadgama; Justine Quach; Wesley L McKeithan; Travis L Biechele; Joseph C Wu; Randall T Moon; P Duc Si Dong; Ioannis Karakikes; John R Cashman; Mark Mercola

doi:10.1016/j.chembiol.2021.01.001

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.

Authors

Jiongjia Cheng¹, Masanao Tsuda², Karl Okolotowicz¹, Mary Dwyer¹, Paul J Bushway³, Alexandre R Colas², Joseph J Lancman², Dennis Schade⁴, Isaac Perea-Gil⁵, Arne A N Bruyneel⁵, Jaechol Lee⁵, Nirmal Vadgama⁵, Justine Quach¹, Wesley L McKeithan⁶, Travis L Biechele⁷, Joseph C Wu⁸, Randall T Moon⁷, P Duc Si Dong², Ioannis Karakikes⁹, John R Cashman², Mark Mercola¹⁰

Affiliations

¹ Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA.
² Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
³ Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; University of California, San Diego, San Diego, CA 92093, USA.
⁴ Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121, USA; Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76, Kiel, Germany.
⁵ Cardiovascular Institute, Stanford University, 240 Pasteur Drive, Palo Alto, CA 94305, USA.
⁶ Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Cardiovascular Institute, Stanford University, 240 Pasteur Drive, Palo Alto, CA 94305, USA.
⁷ Department of Pharmacology, University of Washington, Seattle, WA 98105, USA.
⁸ Cardiovascular Institute, Stanford University, 240 Pasteur Drive, Palo Alto, CA 94305, USA; Department of Medicine, Stanford University, 240 Pasteur Drive, Palo Alto, CA 94305, USA.
⁹ Cardiovascular Institute, Stanford University, 240 Pasteur Drive, Palo Alto, CA 94305, USA; Department of Cardiothoracic Surgery, Stanford University, 240 Pasteur Drive, Palo Alto, CA 94305, USA.
¹⁰ Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; University of California, San Diego, San Diego, CA 92093, USA; Cardiovascular Institute, Stanford University, 240 Pasteur Drive, Palo Alto, CA 94305, USA; Department of Medicine, Stanford University, 240 Pasteur Drive, Palo Alto, CA 94305, USA. Electronic address: [email protected].

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding