An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway
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Ημερομηνία
Τίτλος Εφημερίδας
Περιοδικό ISSN
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Εκδότης
Περίληψη
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Είδος περιοδικού
peer-reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
J Cell Biol
Όνομα βιβλίου
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Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
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.
Περιγραφή
Λέξεις-κλειδιά
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
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
http://www.ncbi.nlm.nih.gov/pubmed/16103228
http://jcb.rupress.org/content/170/4/607.full.pdf
http://jcb.rupress.org/content/170/4/607.full.pdf
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής