An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway (Journal article)

Shin, H. W./ Hayashi, M./ Christoforidis, S./ Lacas-Gervais, S./ Hoepfner, S./ Wenk, M. R./ Modregger, J./ Uttenweiler-Joseph, S./ Wilm, M./ Nystuen, A./ Frankel, W. N./ Solimena, M./ De Camilli, P./ Zerial, M.

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 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.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Keywords: Animals,Astrocytes/cytology/metabolism,Brain/metabolism,Catalysis,Cell Compartmentation,Chromatography, Affinity,Down-Regulation/genetics,*Endocytosis,Enzyme Activation,HeLa Cells,Humans,Mice,NIH 3T3 Cells,Phosphatidylinositol 3-Kinases/metabolism,Phosphatidylinositol Phosphates/metabolism,Phosphatidylinositols/*metabolism,Phosphoprotein Phosphatases/genetics/metabolism,Protein Binding,Protein Transport,Serum,Transferrin/metabolism,rab5 GTP-Binding Proteins/isolation & purification/*metabolism
ISSN: 0021-9525
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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