Increasing β-catenin/Wnt3A activity levels drive mechanical strain-induced cell cycle progression through mitosis

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Abstract

Mechanical force and Wnt signaling activate β-catenin-mediated transcription to promote proliferation and tissue expansion. However, it is unknown whether mechanical force and Wnt signaling act independently or synergize to activate β-catenin signaling and cell division. We show that mechanical strain induced Src-dependent phosphorylation of Y654 β-catenin and increased β-catenin-mediated transcription in mammalian MDCK epithelial cells. Under these conditions, cells accumulated in S/G2 (independent of DNA damage) but did not divide. Activating β-catenin through Casein Kinase I inhibition or Wnt3A addition increased β-catenin-mediated transcription and strain-induced accumulation of cells in S/G2. Significantly, only the combination of mechanical strain and Wnt/β-catenin activation triggered cells in S/G2 to divide. These results indicate that strain-induced Src phosphorylation of β-catenin and Wnt-dependent β-catenin stabilization synergize to increase β-catenin-mediated transcription to levels required for mitosis. Thus, local Wnt signaling may fine-tune the effects of global mechanical strain to restrict cell divisions during tissue development and homeostasis.

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Blair W Benham-Pyle

Program in Cancer Biology, Stanford University, Stanford, United States

Competing interests
No competing interests declared.
Joo Yong Sim

Electronics and Telecommunications Research Institute, Daejeon, Republic of Korea

Competing interests
No competing interests declared.
Kevin C Hart

Department of Biology, Stanford University, Stanford, United States

Competing interests
No competing interests declared.
Beth L Pruitt

Stanford Cardiovascular Institute, Stanford University, Stanford, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-4861-2124
William James Nelson

Program in Cancer Biology, Stanford University, Stanford, United States

For correspondence
wjnelson@stanford.edu

Competing interests
William James Nelson, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0003-3039-3776

Funding

National Science Foundation (1136790)

Beth L Pruitt
William James Nelson

National Science Foundation (Graduate Student Fellowship)

Blair W Benham-Pyle

National Institutes of Health (T32GM007276)

Kevin C Hart

National Institutes of Health (11R35GM118064-01)

William James Nelson

Stanford University (Bio-X Graduate Fellowship)

Joo Yong Sim

Stanford University (Bio-X Graduate Fellowship)

Kevin C Hart

Stanford University (Lieberman Graduate Fellowship)

Blair W Benham-Pyle

National Science Foundation (DGE-114747)

William James Nelson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.