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

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

SUBMITTER: Benham-Pyle BW 

PROVIDER: S-EPMC5104517 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature