1. An FAK-YAP-mTOR Signaling Axis Regulates Stem Cell-Based Tissue Renewal in Mice
- Author
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Hu, Jimmy Kuang-Hsien, Du, Wei, Shelton, Samuel J, Oldham, Michael C, DiPersio, C Michael, and Klein, Ophir D
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Stem Cell Research - Nonembryonic - Non-Human ,Regenerative Medicine ,Stem Cell Research ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Adaptor Proteins ,Signal Transducing ,Animals ,Cell Cycle Proteins ,Cell Differentiation ,Cell Proliferation ,Focal Adhesion Kinase 1 ,Incisor ,Mice ,Mice ,Transgenic ,Phosphoproteins ,Signal Transduction ,Stem Cells ,TOR Serine-Threonine Kinases ,YAP-Signaling Proteins ,CDC42 ,FAK ,ITGA3 ,PP1A ,TAZ ,YAP ,adult stem cells ,epithelium ,tooth ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - 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.
- Published
- 2017