An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway

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dc.contributor.authorShin, H. W.en
dc.contributor.authorHayashi, M.en
dc.contributor.authorChristoforidis, S.en
dc.contributor.authorLacas-Gervais, S.en
dc.contributor.authorHoepfner, S.en
dc.contributor.authorWenk, M. R.en
dc.contributor.authorModregger, J.en
dc.contributor.authorUttenweiler-Joseph, S.en
dc.contributor.authorWilm, M.en
dc.contributor.authorNystuen, A.en
dc.contributor.authorFrankel, W. N.en
dc.contributor.authorSolimena, M.en
dc.contributor.authorDe Camilli, P.en
dc.contributor.authorZerial, M.en
dc.date.accessioned2015-11-24T19:36:35Z
dc.date.available2015-11-24T19:36:35Z
dc.identifier.issn0021-9525-
dc.identifier.urihttps://olympias.lib.uoi.gr/jspui/handle/123456789/23903
dc.rightsDefault Licence-
dc.subjectAnimalsen
dc.subjectAstrocytes/cytology/metabolismen
dc.subjectBrain/metabolismen
dc.subjectCatalysisen
dc.subjectCell Compartmentationen
dc.subjectChromatography, Affinityen
dc.subjectDown-Regulation/geneticsen
dc.subject*Endocytosisen
dc.subjectEnzyme Activationen
dc.subjectHeLa Cellsen
dc.subjectHumansen
dc.subjectMiceen
dc.subjectNIH 3T3 Cellsen
dc.subjectPhosphatidylinositol 3-Kinases/metabolismen
dc.subjectPhosphatidylinositol Phosphates/metabolismen
dc.subjectPhosphatidylinositols/*metabolismen
dc.subjectPhosphoprotein Phosphatases/genetics/metabolismen
dc.subjectProtein Bindingen
dc.subjectProtein Transporten
dc.subjectSerumen
dc.subjectTransferrin/metabolismen
dc.subjectrab5 GTP-Binding Proteins/isolation & purification/*metabolismen
dc.titleAn enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathwayen
heal.abstractGeneration 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 PI3Kbeta, 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-kinasebeta (PI3Kbeta), 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.en
heal.accesscampus-
heal.fullTextAvailabilityTRUE-
heal.identifier.primary10.1083/jcb.200505128-
heal.identifier.secondaryhttp://www.ncbi.nlm.nih.gov/pubmed/16103228-
heal.identifier.secondaryhttp://jcb.rupress.org/content/170/4/607.full.pdf-
heal.journalNameJ Cell Biolen
heal.journalTypepeer-reviewed-
heal.languageen-
heal.publicationDate2005-
heal.recordProviderΠανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικήςel
heal.typejournalArticle-
heal.type.elΆρθρο Περιοδικούel
heal.type.enJournal articleen

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