The relationship between ER–multivesicular body membrane contacts and the ESCRT machinery

2012 ◽  
Vol 40 (2) ◽  
pp. 464-468 ◽  
Author(s):  
Emily R. Eden ◽  
Thomas Burgoyne ◽  
James R. Edgar ◽  
Alexander Sorkin ◽  
Clare E. Futter
Keyword(s):  
Catalytic Domain ◽  
Tyrosine Phosphatase ◽  
Growth Factor Receptor ◽  
Multivesicular Body ◽  
Endosomal Sorting ◽  
Membrane Contact Sites ◽  
Escrt Machinery ◽  
Membrane Contacts ◽  
Epidermal Growth ◽  
The Relationship

Activated EGFR (epidermal growth factor receptor) undergoes ESCRT (endosomal sorting complex required for transport)-mediated sorting on to ILVs (intraluminal vesicles) of endosomes before degradation in the lysosome. Sorting of endocytosed EGFR on to ILVs removes the catalytic domain of the EGFR from the cytoplasm, resulting in termination of receptor signalling. EGFR signalling is also subject to down-regulation through receptor dephosphorylation by the ER (endoplasmic reticulum)-localized PTP1B (protein tyrosine phosphatase 1B). PTP1B on the cytoplasmic face of the ER interacts with endocytosed EGFR via direct membrane contacts sites between the ER and endosomes. In the present paper, we review the relationship between ER–endosome membrane contact sites and ILV formation, and their potential role in the regulation of EGFR sorting on to ILVs, through PTP1B-mediated dephosphorylation of both EGFR and components of the ESCRT machinery.

scholarly journals VPS37A directs ESCRT recruitment for phagophore closure

2019 ◽  
Vol 218 (10) ◽  
pp. 3336-3354 ◽  
Author(s):  
Yoshinori Takahashi ◽  
Xinwen Liang ◽  
Tatsuya Hattori ◽  
Zhenyuan Tang ◽  
Haiyan He ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Growth Factor Receptor ◽  
Multivesicular Body ◽  
Regulatory Mechanisms ◽  
Endosomal Sorting ◽  
Aaa Atpase ◽  
Escrt Machinery ◽  
Genome Wide ◽  
A Genome ◽  
Epidermal Growth

The process of phagophore closure requires the endosomal sorting complex required for transport III (ESCRT-III) subunit CHMP2A and the AAA ATPase VPS4, but their regulatory mechanisms remain unknown. Here, we establish a FACS-based HaloTag-LC3 autophagosome completion assay to screen a genome-wide CRISPR library and identify the ESCRT-I subunit VPS37A as a critical component for phagophore closure. VPS37A localizes on the phagophore through the N-terminal putative ubiquitin E2 variant domain, which is found to be required for autophagosome completion but dispensable for ESCRT-I complex formation and the degradation of epidermal growth factor receptor in the multivesicular body pathway. Notably, loss of VPS37A abrogates the phagophore recruitment of the ESCRT-I subunit VPS28 and CHMP2A, whereas inhibition of membrane closure by CHMP2A depletion or VPS4 inhibition accumulates VPS37A on the phagophore. These observations suggest that VPS37A coordinates the recruitment of a unique set of ESCRT machinery components for phagophore closure in mammalian cells.

scholarly journals Roles for ER:endosome membrane contact sites in ligand-stimulated intraluminal vesicle formation

2018 ◽  
Vol 46 (5) ◽  
pp. 1055-1062 ◽  
Author(s):  
Louise H. Wong ◽  
Emily R. Eden ◽  
Clare E. Futter
Keyword(s):  
Membrane Proteins ◽  
Mammalian Cells ◽  
Tyrosine Phosphatase ◽  
Endosomal Sorting ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contacts ◽  
Epidermal Growth ◽  
Membrane Contact ◽  
Multivesicular Endosomes

Multivesicular endosomes/bodies (MVBs) sort membrane proteins between recycling and degradative pathways. Segregation of membrane proteins onto intraluminal vesicles (ILVs) of MVBs removes them from the recycling pathway and facilitates their degradation following fusion of MVBs with lysosomes. Sorting of many cargos onto ILVs depends on the ESCRT (Endosomal Sorting Complex Required for Transport) machinery, although ESCRT-independent mechanisms also exist. In mammalian cells, efficient sorting of ligand-stimulated epidermal growth factor receptors onto ILVs also depends on the tyrosine phosphatase, PTP1B, an ER-localised enzyme that interacts with endosomal targets at membrane contacts between MVBs and the ER. This review focuses on the potential roles played by ER:MVB membrane contact sites in regulating ESCRT-dependent ILV formation.

scholarly journals Dissecting the role of His domain protein tyrosine phosphatase/PTPN23 and ESCRTs in sorting activated epidermal growth factor receptor to the multivesicular body

2018 ◽  
Vol 46 (5) ◽  
pp. 1037-1046 ◽  
Author(s):  
Lydia Tabernero ◽  
Philip Woodman
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Growth Factor Receptor ◽  
Multivesicular Body ◽  
Protein Tyrosine ◽  
Epidermal Growth ◽  
Domain Protein

Sorting of activated epidermal growth factor receptor (EGFR) into intraluminal vesicles (ILVs) within the multivesicular body (MVB) is an essential step during the down-regulation of the receptor. The machinery that drives EGFR sorting attaches to the cytoplasmic face of the endosome and generates vesicles that bud into the endosome lumen, but somehow escapes encapsulation itself. This machinery is termed the ESCRT (endosomal sorting complexes required for transport) pathway, a series of multi-protein complexes and accessory factors first identified in yeast. Here, we review the yeast ESCRT pathway and describe the corresponding components in mammalian cells that sort EGFR. One of these is His domain protein tyrosine phosphatase (HD-PTP/PTPN23), and we review the interactions involving HD-PTP and ESCRTs. Finally, we describe a working model for how this ESCRT pathway might overcome the intrinsic topographical problem of EGFR sorting to the MVB lumen.

ESCRT proteins, endosome organization and mitogenic receptor down-regulation

2009 ◽  
Vol 37 (1) ◽  
pp. 146-150 ◽  
Author(s):  
Philip Woodman
Keyword(s):  
Growth Factor Receptor ◽  
Multivesicular Body ◽  
Early Endosome ◽  
Tyrosine Kinase Receptors ◽  
Physical Separation ◽  
Endosomal Sorting ◽  
Associated Proteins ◽  
Epidermal Growth ◽  
Detailed Function ◽  
Subsequent Incorporation

Mitogenic tyrosine kinase receptors such as the EGFR (epidermal growth factor receptor) are endocytosed once they are activated at the cell surface. After reaching the early endosome, they are ubiquitinated within their cytosolic domain and are consequently sorted away from recycling receptors. They are then incorporated into intraluminal vesicles within the MVB (multivesicular body) en route to the lysosome, where they are degraded. MVB formation requires the stabilization of the vacuolar domain of the early endosome, the segregation of degradative cargo within this domain (with subsequent incorporation of receptors such as EGFR into intraluminal vesicles) and the physical separation and movement of this domain away from the tubular regions of the early endosome. How these different aspects of MVB biogenesis are coupled is unknown, but ESCRTs (endosomal sorting complexes required for transport) have been identified as key molecular players in driving mitogenic receptor sequestration and formation of intraluminal vesicles. The present review summarizes recent findings within the field and from our laboratory regarding the detailed function of ESCRTs and associated proteins in driving the ubiquitin-dependent sorting of EGFR and in maintaining the domain organization of the early endosome.

scholarly journals Distinct Roles for Tsg101 and Hrs in Multivesicular Body Formation and Inward Vesiculation

2006 ◽  
Vol 17 (8) ◽  
pp. 3469-3483 ◽  
Author(s):  
M. Razi ◽  
C. E. Futter
Keyword(s):  
Growth Factor ◽  
Mammalian Cells ◽  
Susceptibility Gene ◽  
Growth Factor Receptor ◽  
Multivesicular Body ◽  
Early Endosome ◽  
Endosomal Sorting ◽  
Epidermal Growth ◽  
Tumor Susceptibility Gene ◽  
Hepatocyte Growth

In mammalian cells, epidermal growth factor (EGF) stimulation promotes multivesicular body (MVB) formation and inward vesiculation within MVB. Annexin 1 is required for EGF-stimulated inward vesiculation but not MVB formation, demonstrating that MVB formation (the number of MVBs/unit cytoplasm) and inward vesiculation (the number of internal vesicles/MVB) are regulated by different mechanisms. Here, we show that EGF-stimulated MVB formation requires the tumor susceptibility gene, Tsg101, a component of the ESCRT (endosomal sorting complex required for transport) machinery. Depletion of Tsg101 potently inhibits EGF degradation and MVB formation and causes the vacuolar domains of the early endosome to tubulate. Although Tsg101 depletion inhibits MVB formation and alters the morphology of the early endosome in unstimulated cells, these effects are much greater after EGF stimulation. In contrast, depletion of hepatocyte growth factor receptor substrate (Hrs) only modestly inhibits EGF degradation, does not induce tubulation of the early endosome, and causes the generation of enlarged MVBs that retain the ability to fuse with the lysosome. Together, these results indicate that Tsg101 is required for the formation of stable vacuolar domains within the early endosome that develop into MVBs and Hrs is required for the accumulation of internal vesicles within MVBs and that both these processes are up-regulated by EGF stimulation.

TP53 Germline Mutations are Associated with HR+/HER2+ in BRCA1/2-Negative Early-Onset Breast Cancer in China

2022 ◽  
Author(s):  
Lili Chen ◽  
Meng Huang ◽  
Minyan Chen ◽  
Yuxiang Lin ◽  
Jing Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Onset ◽  
Tp53 Mutation ◽  
Sporadic Breast Cancer ◽  
Molecular Subtype ◽  
Growth Factor Receptor ◽  
Early Onset Breast Cancer ◽  
Her 2 ◽  
Epidermal Growth ◽  
The Relationship

Abstract Background: Except for BRCA1/2, there is no data on the relationship between genetic counseling for the range of mutations and early-onset breast cancer populations. We looked for a link between inherited genes and the molecular subtype of early-onset breast cancer.Methods: We genotyped 1214 individuals with early-onset sporadic breast cancer (age≤40 years) who were BRCA1/2-negative in 3 genes: TP53, PALB2, and RECQL. We focus on the immunohistochemistry characteristics that are unique to each patient. Results: The mutation rates of TP53, PALB2, and RECQL in 1214 BRCA-negative young individuals were 4/1214(0.33%), 8/1214(0.66%), 2/1214(0.16%), respectively. The fact that the TP53 mutation rate was 3.49% among estrogen receptor-and/or progesterone receptor-positive, human epidermal growth factor receptor 2 (HER-2) amplification patients under the age of 35 (P<0.001) was particularly noteworthy. Conclusion: According to the findings, TP53 genetic testing should focus on women under 35 with HR-positive and HER2-positve IDC patients.

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