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Published 15 August 2005. doi:10.1083/jcb.200505128
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 4, 607-618
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Article

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

Hye-Won Shin1, Mitsuko Hayashi3, Savvas Christoforidis2, Sandra Lacas-Gervais4, Sebastian Hoepfner1, Markus R. Wenk3, Jan Modregger3, Sandrine Uttenweiler-Joseph5, Matthias Wilm5, Arne Nystuen6, Wayne N. Frankel6, Michele Solimena4, Pietro De Camilli3, and Marino Zerial1

1 Max-Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
2 Laboratory of Biological Chemistry, Medical School, University of Ioannina, Ioannina 45110, Greece
3 Department of Cell Biology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510
4 Medical Theoretical Center, Medical School, University of Technology of Dresden, 01307 Dresden, Germany
5 European Molecular Biology Laboratory, 69117 Heidelberg, Germany
6 The Jackson Laboratory, Bar Harbor, ME 04609

Correspondence to M. Zerial: zerial{at}mpi-cbg.de

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 PI3Kß, 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-kinaseß (PI3Kß), 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.

Abbreviations used in this paper: 4-Pase, a type I {alpha} PtdIns(3,4)P2 4-phosphatase; 5-Pase, type II inositol 5-phosphatase; OCRL, oculocerebrorenal syndrome of Lowe; PI, phosphoinositide; PI3-K, phosphoinositide-3-kinase; PtdIns, phosphatidylinositol; wt, wild-type.

S. Uttenweiler-Joseph's present address is IPBS, CNRS, 31077 Toulouse Cedex, France.

H.-W. Shin's present address is Dept. of Physiological Chemistry, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.

M.R. Wenk's present address is Depts. of Biochemistry and Biological Sciences, National University of Singapore, Singapore 117597, Republic of Singapore.


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