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

被引：26

作者：

Miller, Daniel S. J. ^{[1
]}

Bloxham, Robert D. ^{[1
]}

Jiang, Ming ^{[2
]}

Gori, Ilaria ^{[1
]}

Saunders, Rebecca E. ^{[2
]}

Das, Debipriya ^{[1
,4
]}

Chakravarty, Probir ^{[3
]}

Howell, Michael ^{[2
]}

Hill, Caroline S. ^{[1
]}

机构：

[1] Francis Crick Inst, Dev Signalling Lab, 1 Midland Rd, London NW1 1AT, England

[2] Francis Crick Inst, High Throughput Screening Lab, 1 Midland Rd, London NW1 1AT, England

[3] Francis Crick Inst, Bioinformat & Biostat Facil, 1 Midland Rd, London NW1 1AT, England

[4] Francis Crick Inst, Flow Cytometry Facil, 1 Midland Rd, London NW1 1AT, England

来源：

CELL REPORTS | 2018年 / 25卷 / 07期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; I RECEPTOR; HD-PTP; CANCER PROGRESSION; UBIQUITIN LIGASE; ENDOCYTOSIS; COMPLEXES; CELLS; SMURF2; SMADS;

D O I：

10.1016/j.celrep.2018.10.056

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 beta (TGF-beta) 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-beta 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.

引用

页码：1841 / +

页数：20

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