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

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

Author information

1
Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
3
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Brain Tumor Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY 12208, USA.
5
Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: ophir.klein@ucsf.edu.

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

PMID:
28457749
PMCID:
PMC5501749
DOI:
10.1016/j.stem.2017.03.023
[Indexed for MEDLINE]
Free PMC Article

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