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The UIM domain of Hrs couples receptor sorting to vesicle formation

S. Urbe, Martin Sachse, Paula Row, Christian Preisinger, Francis A Barr, Ger Strous, Judith Klumperman, Michael J Clague

Journal of Cell Science, Volume: 116, Issue: 20, Pages: 4169 - 4179

Swansea University Author: Paula Row

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DOI (Published version): 10.1242/jcs.00723

Abstract

Hepatocyte growth factor regulated tyrosine kinase substrate (Hrs), a main component of the 'bilayered' clathrin coat on sorting endosomes, was originally identified as a substrate of activated tyrosine kinase receptors. We have analysed Hrs phosphorylation in response to epidermal growth...

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Published in: Journal of Cell Science
Published: 2003
Online Access: http://jcs.biologists.org/content/116/20/4169.full.pdf
URI: https://cronfa.swan.ac.uk/Record/cronfa18377
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first_indexed 2014-09-11T01:59:10Z
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spelling 2019-06-24T15:13:40.1219668 v2 18377 2014-09-10 The UIM domain of Hrs couples receptor sorting to vesicle formation 99bb528b2f8fb62aabbdad101d53ba96 Paula Row Paula Row true false 2014-09-10 BMS Hepatocyte growth factor regulated tyrosine kinase substrate (Hrs), a main component of the 'bilayered' clathrin coat on sorting endosomes, was originally identified as a substrate of activated tyrosine kinase receptors. We have analysed Hrs phosphorylation in response to epidermal growth factor (EGF) stimulation and show that the evolutionary conserved tyrosines Y329 and Y334 provide the principal phosphorylation sites. Hrs is proposed to concentrate ubiquitinated receptors within clathrin-coated regions via direct interaction with its UIM (ubiquitin interaction motif) domain. We show that the same UIM domain is necessary for EGF-stimulated tyrosine phosphorylation of Hrs. Over-expression of wild-type Hrs or a double mutant, Y329/334F, defective in EGF-dependent phosphorylation, both substantially retard EGF receptor (EGFR) degradation by inhibiting internal vesicle formation and thereby preventing EGFR incorporation into lumenal vesicles of the multivesicular bodies. In contrast, mutation or deletion of the Hrs-UIM domain strongly suppresses this effect. In addition the UIM-deletion and point mutants are also observed on internal membranes, indicating a failure to dissociate from the endosomal membrane prior to incorporation of the receptor complex into lumenal vesicles. Our data suggest a role for the UIM-domain of Hrs in actively retaining EGFR at the limiting membrane of endosomes as a prelude to lumenal vesicle formation. Journal Article Journal of Cell Science 116 20 4169 4179 Hrs, Endocytosis, Clathrin, Ubiquitin, Phosphorylation 12 9 2003 2003-09-12 10.1242/jcs.00723 http://jcs.biologists.org/content/116/20/4169.full.pdf COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2019-06-24T15:13:40.1219668 2014-09-10T13:34:53.1892203 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine S. Urbe 1 Martin Sachse 2 Paula Row 3 Christian Preisinger 4 Francis A Barr 5 Ger Strous 6 Judith Klumperman 7 Michael J Clague 8
title The UIM domain of Hrs couples receptor sorting to vesicle formation
spellingShingle The UIM domain of Hrs couples receptor sorting to vesicle formation
Paula Row
title_short The UIM domain of Hrs couples receptor sorting to vesicle formation
title_full The UIM domain of Hrs couples receptor sorting to vesicle formation
title_fullStr The UIM domain of Hrs couples receptor sorting to vesicle formation
title_full_unstemmed The UIM domain of Hrs couples receptor sorting to vesicle formation
title_sort The UIM domain of Hrs couples receptor sorting to vesicle formation
author_id_str_mv 99bb528b2f8fb62aabbdad101d53ba96
author_id_fullname_str_mv 99bb528b2f8fb62aabbdad101d53ba96_***_Paula Row
author Paula Row
author2 S. Urbe
Martin Sachse
Paula Row
Christian Preisinger
Francis A Barr
Ger Strous
Judith Klumperman
Michael J Clague
format Journal article
container_title Journal of Cell Science
container_volume 116
container_issue 20
container_start_page 4169
publishDate 2003
institution Swansea University
doi_str_mv 10.1242/jcs.00723
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
url http://jcs.biologists.org/content/116/20/4169.full.pdf
document_store_str 0
active_str 0
description Hepatocyte growth factor regulated tyrosine kinase substrate (Hrs), a main component of the 'bilayered' clathrin coat on sorting endosomes, was originally identified as a substrate of activated tyrosine kinase receptors. We have analysed Hrs phosphorylation in response to epidermal growth factor (EGF) stimulation and show that the evolutionary conserved tyrosines Y329 and Y334 provide the principal phosphorylation sites. Hrs is proposed to concentrate ubiquitinated receptors within clathrin-coated regions via direct interaction with its UIM (ubiquitin interaction motif) domain. We show that the same UIM domain is necessary for EGF-stimulated tyrosine phosphorylation of Hrs. Over-expression of wild-type Hrs or a double mutant, Y329/334F, defective in EGF-dependent phosphorylation, both substantially retard EGF receptor (EGFR) degradation by inhibiting internal vesicle formation and thereby preventing EGFR incorporation into lumenal vesicles of the multivesicular bodies. In contrast, mutation or deletion of the Hrs-UIM domain strongly suppresses this effect. In addition the UIM-deletion and point mutants are also observed on internal membranes, indicating a failure to dissociate from the endosomal membrane prior to incorporation of the receptor complex into lumenal vesicles. Our data suggest a role for the UIM-domain of Hrs in actively retaining EGFR at the limiting membrane of endosomes as a prelude to lumenal vesicle formation.
published_date 2003-09-12T03:21:32Z
_version_ 1763750647238230016
score 11.037056

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