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Cell Rep. 2018 Nov 13;25(7):1841-1855.e5. doi: 10.1016/j.celrep.2018.10.056.

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

Author information

1
Developmental Signalling Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
2
High Throughput Screening Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
3
Bioinformatics and Biostatistics Facility, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
4
Developmental Signalling Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: caroline.hill@crick.ac.uk.

Abstract

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.

KEYWORDS:

ESCRT machinery; SMAD2; TGF-β; epithelial-to-mesenchymal transition; receptor trafficking; signaling dynamics

PMID:
30428352
DOI:
10.1016/j.celrep.2018.10.056
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