The Dynamics of TGF-β Signaling Are Dictated by Receptor Trafficking via the ESCRT Machinery

Abstract

Summary: Signal transduction pathways stimulated by secreted growth factors are tightly regulated at multiple levels between the cell surface and the nucleus. The trafficking of cell surface receptors is emerging as a key step for regulating appropriate cellular responses, with perturbations in this process contributing to human diseases, including cancer. For receptors recognizing ligands of the transforming growth factor β (TGF-β) family, little is known about how trafficking is regulated or how this shapes signaling dynamics. Here, using whole genome small interfering RNA (siRNA) screens, we have identified the ESCRT (endosomal sorting complex required for transport) machinery as a crucial determinant of signal duration. Downregulation of ESCRT components increases the outputs of TGF-β signaling and sensitizes cells to low doses of ligand in their microenvironment. This sensitization drives an epithelial-to-mesenchymal transition (EMT) in response to low doses of ligand, and we demonstrate a link between downregulation of the ESCRT machinery and cancer survival. : Miller et al. demonstrate, using whole genome siRNA screening, that TGF-β receptors are targeted for degradation by the ESCRT machinery. Inhibiting ESCRT components upregulates long-term TGF-β signaling and enhances functional outputs of the pathway to sensitize cells to low levels of ligand in the micro-environment. Keywords: epithelial-to-mesenchymal transition, ESCRT machinery, receptor trafficking, signaling dynamics, SMAD2, TGF-β