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

Abstract

Summary Tissue homeostasis requires 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 a 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 proliferation of TA cells. These findings thus reveal a YAP/TAZ signaling mechanism that coordinates stem cell expansion and differentiation during organ renewal.

Tissue Mechanical Forces and Evolutionary Developmental Changes Act Through Space and Time to Shape Tooth Morphology and Function

“…Thus, whether occlusal dynamics and mechanical force influence stem cell proliferation in other tooth and cell types, such as epithelial stem cells of adult incisors, requires further investigation. Such a relationship would be consistent with the observation that proliferation of these stem cells is regulated through an integrin‐YAP signaling axis capable of mechanotransduction . Further research will clarify these questions and may aid the development of new strategies integrating chemical and mechanical signaling to control dental stem cell proliferation and differentiation for clinical applications.…”

Integrin‐FAK‐CDC42‐PP1A signaling gnaws at YAP/TAZ activity to control incisor stem cells

“…Analyses of YAP/TAZ activity in a variety of tissues have demonstrated common and differing roles for YAP and TAZ in stem/progenitor cell expansion in development and regeneration. Conditional deletion studies of YAP/TAZ in developing and adult animals have shown the depletion of stem/progenitor cell populations in several organs , including the lung , salivary gland , pancreas , epidermis , and, most recently, the incisors, as demonstrated by Hu et al . The potency of YAP/TAZ for establishing and maintaining lineage specific stem cells has been further demonstrated by the ability of transient YAP or TAZ expression to reprogram differentiated mammary, neural, and pancreatic cells into local tissue specific stem cells with self‐renewal and differentiation capacity .…”

“…The transcriptional effectors YAP and TAZ are increasingly being recognized as central mediators of epithelial stem cell biology, and a wealth of recent studies have been directed at understanding the control and activity of these factors. Recent work by Hu et al has added to this knowledge, as they identify an Integrin‐FAK‐CDC42‐PP1A signaling cascade that directs nuclear YAP/TAZ activity in stem cell populations of the mouse incisor, and define convergence on mTORC1 signaling as an important mediator of the proliferation of these cells. Here, we review recent studies on YAP/TAZ function and regulation in epithelial tissue‐specific stem cells, merging the Hu et al study together with our current knowledge of YAP/TAZ.…”

The role of Hippo signaling pathway and mechanotransduction in tuning embryoid body formation and differentiation

“…Moreover, PDK1, which is downstream of PI3K, can then disrupt the core kinase cassette and inhibit Hippo signaling (Kim & Gumbiner, 2015). An alternative mechanism is also described for the FAK‐linked regulation of YAP, involving the dephosphorylation of Ser397 by the protein phosphatase PP1A (Hu et al, 2017). Src can also promote YAP activity by its direct phosphorylation in addition to phosphorylating and inactivating the LATS (P. Li et al, 2016; Si et al, 2017; Taniguchi et al, 2015).…”