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

Mechanical force and Wnt signaling activate beta-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 beta-catenin signaling and cell division. We show that mechanical strain induced Src-dependent phosphorylation of Y654 beta-catenin and increased beta-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 beta-catenin through Casein Kinase I inhibition or Wnt3A addition increased beta-catenin-mediated transcription and strain-induced accumulation of cells in S/G2. Significantly, only the combination of mechanical strain and Wnt/beta-catenin activation triggered cells in S/G2 to divide. These results indicate that strain-induced Src phosphorylation of beta-catenin and Wnt-dependent beta-catenin stabilization synergize to increase beta-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.