We and others have shown that the Hippo pathway effectors TAZ and YAP direct Smad activity to regulate TGFβ family-induced cellular responses in stem cell and cancer biology. In polarized epithelial cells we showed that the Crumbs complex promotes Hippo-dependent cytoplasmic TAZ/YAP localization that restricts TGFβ-induced Smad nuclear accumulation and activity. In this Developmental Cell issue, basal-lateral restriction of TGFβ receptors is proposed as the sole mechanism suppressing Smad signaling in epithelial cells. Here we show that basal recruitment of TGFβ receptors occurs subsequent to Hippo-dependent suppression of Smad activity by cytoplasmic TAZ/YAP. Our results demonstrate that receptor sequestration and Hippo control of activated Smads are distinct events regulating TGFβ signaling in polarized epithelia and raise interesting questions about the function of these pathways in controlling Smad signaling in development, homeostasis, and disease. This Matters Arising Response addresses the Nallet-Staub et al. (2015) Matters Arising, published concurrently in Developmental Cell.
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