Yap1 Acts Downstream of α-Catenin to Control Epidermal Proliferation

• Published in: Cell Vol. 144; no. 5; pp. 782 - 795
• Main Authors: Schlegelmilch, Karin, Mohseni, Morvarid, Kirak, Oktay, Pruszak, Jan, Rodriguez, J. Renato, Zhou, Dawang, Kreger, Bridget T., Vasioukhin, Valera, Avruch, Joseph, Brummelkamp, Thijn R., Camargo, Fernando D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.03.2011
• Subjects: 14-3-3 Proteins - metabolism; Adaptor Proteins, Signal Transducing - metabolism; alpha Catenin - metabolism; Animals; Cell Cycle Proteins; Cell Line; Cell Proliferation; Epidermal Cells; epidermis (animal); Epidermis - metabolism; mammals; Mice; phosphoprotein phosphatase; Phosphoproteins - metabolism; protein phosphorylation; protein-protein interactions; signal transduction; stem cells; transcription (genetics); transcription factors
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.02.031

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. [Display omitted] ► Yap is a critical modulator of epidermal stem cell proliferation ► In epidermis, Yap's function is mediated by TEAD transcription factors ► α-catenin is a cell density sensor regulating Yap activity in the epidermis ► A 14-3-3/α-catenin complex limits PP2A-mediated Yap dephosphorylation