Dissecting the Functional Selectivity of TGFβ Signaling Pathway Components Using Genome Engineered Human Organotypic Skin Models

Transforming growth factor β (TGFβ) signaling is essential for cell growth and differentiation. Yet, the role of the individual TGFβ signaling components in human tissue homeostasis and transformation is still not completely understood. Here we applied a combined strategy of genetic engineering, a human organotypic 3D skin model, and global quantitative proteomics and phosphoproteomics to dissect the importance of essential components of the TGFβ signaling pathway. Our results show that loss of Smad4-dependent TGFβ signaling affected skin homeostasis through regulation of ECM expression and cell cycle control. In contrast, deletion of TGFβRII resulting in the combined loss of Smad4-dependent and independent TGFβ signaling induced invasive growth through activation of p38 and ERK signaling. The study provides a framework for exploration of signaling pathways with genetic engineering, human 3D tissue models, and with global proteomics and phosphoproteomics.