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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Hye Won Shin - , Max Planck Institute of Molecular Cell Biology and Genetics, Kyoto University (Author)
  • Mitsuko Hayashi - , Yale University (Author)
  • Savvas Christoforidis - , University of Ioannina (Author)
  • Sandra Lacas-Gervais - , Experimental Center of the Faculty of Medicine (Author)
  • Sebastian Hoepfner - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Markus R. Wenk - , Yale University, National University of Singapore (Author)
  • Jan Modregger - , Yale University (Author)
  • Sandrine Uttenweiler-Joseph - , European Molecular Biology Laboratory (EMBL) Heidelberg, IPBS Institut de Pharmacologie et de Biologie Structurale (Author)
  • Matthias Wilm - , European Molecular Biology Laboratory (EMBL) Heidelberg (Author)
  • Arne Nystuen - , Jackson Laboratory (Author)
  • Wayne N. Frankel - , Jackson Laboratory (Author)
  • Michele Solimena - , Experimental Center of the Faculty of Medicine (Author)
  • Pietro De Camilli - , Yale University (Author)
  • Marino Zerial - , Max Planck Institute of Molecular Cell Biology and Genetics (Author)

Abstract

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 Ptd-Ins(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.

Details

Original languageEnglish
Pages (from-to)607-618
Number of pages12
JournalJournal of Cell Biology
Volume170
Issue number4
Publication statusPublished - 15 Aug 2005
Peer-reviewedYes

External IDs

PubMed 16103228

Keywords

ASJC Scopus subject areas