An FAK-YAP-mTOR Signaling Axis Regulates Stem Cell-Based Tissue Renewal in Mice

Cell Stem Cell. 2017 Jul 6;21(1):91-106.e6. doi: 10.1016/j.stem.2017.03.023. Epub 2017 Apr 27.

Abstract

Tissue homeostasis requires the production of newly differentiated cells from resident adult stem cells. Central to this process is the expansion of undifferentiated intermediates known as transit-amplifying (TA) cells, but how stem cells are triggered to enter this proliferative TA state remains an important open question. Using the continuously growing mouse incisor as a model of stem cell-based tissue renewal, we found that the transcriptional cofactors YAP and TAZ are required both to maintain TA cell proliferation and to inhibit differentiation. Specifically, we identified a pathway involving activation of integrin α3 in TA cells that signals through an LATS-independent FAK/CDC42/PP1A cascade to control YAP-S397 phosphorylation and nuclear localization. This leads to Rheb expression and potentiates mTOR signaling to drive the proliferation of TA cells. These findings thus reveal a YAP/TAZ signaling mechanism that coordinates stem cell expansion and differentiation during organ renewal.

Keywords: CDC42; FAK; ITGA3; PP1A; TAZ; YAP; adult stem cells; epithelium; tooth.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation*
  • Cell Proliferation*
  • Focal Adhesion Kinase 1 / genetics
  • Focal Adhesion Kinase 1 / metabolism*
  • Incisor / cytology
  • Incisor / metabolism*
  • Mice
  • Mice, Transgenic
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Signal Transduction*
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • Yap protein, mouse
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Focal Adhesion Kinase 1
  • Ptk2 protein, mouse