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- Title
An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway.
- Authors
Hye-Won Shin; 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
- 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 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.
- Publication
Journal of Cell Biology, 2005, Vol 170, Issue 4, p607
- ISSN
0021-9525
- Publication type
Academic Journal
- DOI
10.1083/jcb.200505128