Yap1 Acts Downstream of α-Catenin to Control Epidermal Proliferation

Abstract

During development and regeneration, proliferation of tissue-specific stem cells is tightly controlled to produce organs of a predetermined size. The molecular determinants of this process remain poorly understood. Here, we investigate the function of Yap1, the transcriptional effector of the Hippo signaling pathway, in skin biology. Using gain- and loss-of-function studies we show that Yap1 is a critical modulator of epidermal stem cell proliferation and tissue expansion. Yap1 mediates this effect through interaction with TEAD transcription factors. Additionally, our studies reveal that α-catenin, a molecule previously implicated in tumor suppression and cell density sensing in the skin, is an upstream negative regulator of Yap1. α-catenin controls Yap1 activity and phosphorylation by modulating its interaction with 14-3-3 and the PP2A phosphatase. Together, these data identify Yap1 as a determinant of the proliferative capacity of epidermal stem cells and as an important effector of a ‘crowd control’ molecular circuitry in mammalian skin.

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…The role of the Hippo pathway in skin progenitors has also been studied. Similar to intestine and brain, the expression and nuclear localization of YAP is also significantly higher in the basal epidermis progenitor compartment (Schlegelmilch et al, 2011). Nuclear YAP progressively declines with age and correlates with proliferative potential of progenitors .…”

“…YAP and TAZ also interact with another tight junction protein ZO-2, which was reported to increase nuclear localization of YAP and tightjunction localization of TAZ, respectively Remue et al, 2010). Interestingly, a major adherens junction protein alpha-catenin could also bind to and inhibit YAP by mediating its cell-cell junction and cytoplasmic localizations (Schlegelmilch et al, 2011;Silvis et al, 2011). Clearly, protein-protein interaction is important in the physiological regulation of YAP.…”

“…Nuclear YAP progressively declines with age and correlates with proliferative potential of progenitors . K14-Cre-driven expression of YAP caused marked expansion of basal progenitor cells © Higher Education Press and Springer-Verlag Berlin Heidelberg 2012 (Schlegelmilch et al, 2011;Zhang et al, 2011). Staining of specific markers suggested that these cells were actively proliferating.…”

Merlin: a tumour suppressor with functions at the cell cortex and in the nucleus

“…Overexpression of Merlin promotes phosphorylation and nuclear extrusion of YAP, a downstream target of the Hippo kinase cascade [33,94], which functions as a co-activator of TEAD transcription factors (Fig 3B; [97,98]). By contrast, silencing of Merlin induces TEAD-dependent transcription [92]. Two stud- [92].…”

“…By contrast, silencing of Merlin induces TEAD-dependent transcription [92]. Two stud- [92]. Two stud-.…”