The phox homology domain of phospholipase D activates dynamin GTPase activity and accelerates EGFR endocytosis
- 16 April 2006
- journal article
- letter
- Published by Springer Science and Business Media LLC in Nature
- Vol. 8 (5), 477-484
- https://doi.org/10.1038/ncb1401
Abstract
Dynamin is a large GTP-binding protein that mediates endocytosis by hydrolyzing GTP1,2,3. Previously, we reported that phospholipase D2 (PLD2) interacts with dynamin in a GTP-dependent manner4. This implies that PLD may regulate the GTPase cycle of dynamin. Here, we show that PLD functions as a GTPase activating protein (GAP) through its phox homology domain (PX), which directly activates the GTPase domain of dynamin, and that the arginine residues in the PLD–PX are vital for this GAP function. Moreover, wild-type PLD–PX, but not mutated PLD–PXs defective for GAP function in vitro, increased epidermal growth factor receptor (EGFR) endocytosis at physiological EGF concentrations. In addition, the silencing of PLDs was shown to retard EGFR endocytosis and the addition of wild-type PLDs or lipase-inactive PLDs, but not PLD1 mutants with defective GAP activity for dynamin in vitro, resulted in the recovery of EGFR endocytosis. These findings suggest that PLD, functioning as an intermolecular GAP for dynamin, accelerates EGFR endocytosis. Moreover, we determined that the phox homology domain itself had GAP activity — a novel function in addition to its role as a binding motif for proteins or lipids.Keywords
This publication has 30 references indexed in Scilit:
- Regulation of phospholipase D2 by GTP-dependent interaction with dynaminAdvances in Enzyme Regulation, 2004
- The Direct Interaction of Phospholipase C-γ1 with Phospholipase D2 Is Important for Epidermal Growth Factor SignalingJournal of Biological Chemistry, 2003
- Regulation of phospholipase DFEBS Letters, 2002
- Dynamin and Its Role in Membrane FissionAnnual Review of Cell and Developmental Biology, 2000
- Cardiac Phospholipase D2 Localizes to Sarcolemmal Membranes and Is Inhibited by α-Actinin in an ADP-ribosylation Factor-reversible MannerPublished by Elsevier BV ,2000
- Mammalian phospholipase D structure and regulationBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 1999
- Dynamin and its partners: a progress reportCurrent Opinion in Cell Biology, 1998
- Dynamin-mediated Internalization of CaveolaeThe Journal of cell biology, 1998
- Phospholipase D2, a distinct phospholipase D isoform with novel regulatory properties that provokes cytoskeletal reorganizationCurrent Biology, 1997
- Human ADP-ribosylation Factor-activated Phosphatidylcholine-specific Phospholipase D Defines a New and Highly Conserved Gene FamilyJournal of Biological Chemistry, 1995