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An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway
Generation and turnover of phosphoinositides (PIs) must be coordinated in a spatial- and temporal-restricted manner. The small GTPase Rab5 interacts with two PI 3-kinases, Vps34 and PI3Kβ, suggesting that it regulates the production of 3-PIs at various stages of the early endocytic pathway. Here, we...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2005
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2171494/ https://www.ncbi.nlm.nih.gov/pubmed/16103228 http://dx.doi.org/10.1083/jcb.200505128 |
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author | Shin, Hye-Won Hayashi, Mitsuko Christoforidis, Savvas Lacas-Gervais, Sandra Hoepfner, Sebastian Wenk, Markus R. Modregger, Jan Uttenweiler-Joseph, Sandrine Wilm, Matthias Nystuen, Arne Frankel, Wayne N. Solimena, Michele De Camilli, Pietro Zerial, Marino |
author_facet | Shin, Hye-Won Hayashi, Mitsuko Christoforidis, Savvas Lacas-Gervais, Sandra Hoepfner, Sebastian Wenk, Markus R. Modregger, Jan Uttenweiler-Joseph, Sandrine Wilm, Matthias Nystuen, Arne Frankel, Wayne N. Solimena, Michele De Camilli, Pietro Zerial, Marino |
author_sort | Shin, Hye-Won |
collection | PubMed |
description | Generation and turnover of phosphoinositides (PIs) must be coordinated in a spatial- and temporal-restricted manner. The small GTPase Rab5 interacts with two PI 3-kinases, Vps34 and PI3Kβ, suggesting that it regulates the production of 3-PIs at various stages of the early endocytic pathway. Here, we discovered that Rab5 also interacts directly with PI 5- and PI 4-phosphatases and stimulates their activity. Rab5 regulates the production of phosphatidylinositol 3-phosphate (PtdIns[3]P) through a dual mechanism, by directly phosphorylating phosphatidylinositol via Vps34 and by a hierarchical enzymatic cascade of phosphoinositide-3-kinaseβ (PI3Kβ), PI 5-, and PI 4-phosphatases. The functional importance of such an enzymatic pathway is demonstrated by the inhibition of transferrin uptake upon silencing of PI 4-phosphatase and studies in weeble mutant mice, where deficiency of PI 4-phosphatase causes an increase of PtdIns(3,4)P2 and a reduction in PtdIns(3)P. Activation of PI 3-kinase at the plasma membrane is accompanied by the recruitment of Rab5, PI 4-, and PI 5-phosphatases to the cell cortex. Our data provide the first evidence for a dual role of a Rab GTPase in regulating both generation and turnover of PIs via PI kinases and phosphatases to coordinate signaling functions with organelle homeostasis. |
format | Text |
id | pubmed-2171494 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2005 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21714942008-03-05 An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway Shin, Hye-Won Hayashi, Mitsuko Christoforidis, Savvas Lacas-Gervais, Sandra Hoepfner, Sebastian Wenk, Markus R. Modregger, Jan Uttenweiler-Joseph, Sandrine Wilm, Matthias Nystuen, Arne Frankel, Wayne N. Solimena, Michele De Camilli, Pietro Zerial, Marino J Cell Biol Research Articles Generation and turnover of phosphoinositides (PIs) must be coordinated in a spatial- and temporal-restricted manner. The small GTPase Rab5 interacts with two PI 3-kinases, Vps34 and PI3Kβ, suggesting that it regulates the production of 3-PIs at various stages of the early endocytic pathway. Here, we discovered that Rab5 also interacts directly with PI 5- and PI 4-phosphatases and stimulates their activity. Rab5 regulates the production of phosphatidylinositol 3-phosphate (PtdIns[3]P) through a dual mechanism, by directly phosphorylating phosphatidylinositol via Vps34 and by a hierarchical enzymatic cascade of phosphoinositide-3-kinaseβ (PI3Kβ), PI 5-, and PI 4-phosphatases. The functional importance of such an enzymatic pathway is demonstrated by the inhibition of transferrin uptake upon silencing of PI 4-phosphatase and studies in weeble mutant mice, where deficiency of PI 4-phosphatase causes an increase of PtdIns(3,4)P2 and a reduction in PtdIns(3)P. Activation of PI 3-kinase at the plasma membrane is accompanied by the recruitment of Rab5, PI 4-, and PI 5-phosphatases to the cell cortex. Our data provide the first evidence for a dual role of a Rab GTPase in regulating both generation and turnover of PIs via PI kinases and phosphatases to coordinate signaling functions with organelle homeostasis. The Rockefeller University Press 2005-08-15 /pmc/articles/PMC2171494/ /pubmed/16103228 http://dx.doi.org/10.1083/jcb.200505128 Text en Copyright © 2005, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Shin, Hye-Won Hayashi, Mitsuko Christoforidis, Savvas Lacas-Gervais, Sandra Hoepfner, Sebastian Wenk, Markus R. Modregger, Jan Uttenweiler-Joseph, Sandrine Wilm, Matthias Nystuen, Arne Frankel, Wayne N. Solimena, Michele De Camilli, Pietro Zerial, Marino An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway |
title | An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway |
title_full | An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway |
title_fullStr | An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway |
title_full_unstemmed | An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway |
title_short | An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway |
title_sort | enzymatic cascade of rab5 effectors regulates phosphoinositide turnover in the endocytic pathway |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2171494/ https://www.ncbi.nlm.nih.gov/pubmed/16103228 http://dx.doi.org/10.1083/jcb.200505128 |
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