title: Increasing β-catenin/Wnt3A activity levels drive mechanical strain-induced cell cycle progression through mitosis.
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.
authors: Program in Cancer Biology, Stanford University, Stanford, United States.
authors: Blair W
authors: BW
authors: Benham-Pyle
authors: Department of Mechanical Engineering, Stanford University, Stanford, United States.
authors: Joo Yong
authors: JY
authors: Sim
authors: Department of Biology, Stanford University, Stanford, United States.
authors: Kevin C
authors: KC
authors: Hart
authors: Department of Mechanical Engineering, Stanford University, Stanford, United States.|Stanford Cardiovascular Institute, Stanford University, Stanford, United States.|Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States.
authors: Beth L
authors: 0000-0002-4861-2124
authors: BL
authors: Pruitt
authors: Program in Cancer Biology, Stanford University, Stanford, United States.|Department of Biology, Stanford University, Stanford, United States.|Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States.
authors: William James
authors: 0000-0003-3039-3776
authors: WJ
authors: Nelson
mesh_terms: D000818:Animals; D004285:Dogs; D061985:Madin Darby Canine Kidney Cells; D055595:Mechanical Phenomena; D008938:Mitosis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D060509:Wnt3A Protein; D051176:beta Catenin; D019061:src-Family Kinases
keywords: Src; Wnt; cell biology; cell cycle; mechanotransduction; none; β-catenin