The dynamics of TGF-β signaling are dictated by receptor trafficking via the ESCRT machinery
journal contributionposted on 2020-09-07, 11:10 authored by Daniel SJ Miller, Robert D Bloxham, Ming Jiang, Ilaria Gori, Rebecca E Saunders, Debipriya Das, Probir Chakravarty, Michael Howell, Caroline S Hill
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.
ESCRT machinerySMAD2TGF-βepithelial-to-mesenchymal transitionreceptor traffickingsignaling dynamicsActivinsAnimalsBone Morphogenetic ProteinsCell LineDown-RegulationEndosomal Sorting Complexes Required for TransportEpithelial-Mesenchymal TransitionGenome, HumanHumansLysosomesMiceMultivesicular BodiesNeoplasmsPhosphorylationPrognosisProtein TransportProteolysisReceptors, Transforming Growth Factor betaSignal TransductionSmad2 ProteinSurvival AnalysisTransforming Growth Factor betaUbiquitin-Protein LigasesUp-RegulationHill FC001095HTSCBLM-ackFC-ackGEP-ack0601 Biochemistry and Cell Biology