Regulation of phospholipase D1 subcellular cycling through coordination of multiple membrane association motifs

Guangwei Du, Yelena M. Altshuller, Nicolas Vitale, Ping Huang, Sylvette Chasserot-Golaz, Andrew J. Morris, Marie France Bader, Michael A. Frohman

Research output: Contribution to journalArticlepeer-review

144 Scopus citations


The signaling enzyme phospholipase D1 (PLD1) facilitates membrane vesicle trafficking. Here, we explore how PLD1 subcellular localization is regulated via Phox homology (PX) and pleckstrin homology (PH) domains and a P14,5P2-binding site critical for its activation. PLD1 localized to perinuclear endosomes and Golgi in COS-7 cells, but on cellular stimulation, translocated to the plasma membrane in an activity-facilitated manner and then returned to the endosomes. The PI4, 5P2-interacting site sufficed to mediate outward translocation and association with the plasma membrane. However, in the absence of PX and PH domains, PLD1 was unable to return efficiently to the endosomes. The PX and PH domains appear to facilitate internalization at different steps. The PH domain drives PLD1 entry into lipid rafts, which we show to be a step critical for internalization. In contrast, the PX domain appears to mediate binding to PI5P, a lipid newly recognized to accumulate in endocytosing vesicles. Finally, we show that the PH domain-dependent translocation step, but not the PX domain, is required for PLD1 to function in regulated exocytosis in PC12 cells. We propose that PLD1 localization and function involves regulated and continual cycling through a succession of subcellular sites, mediated by successive combinations of membrane association interactions.

Original languageEnglish
Pages (from-to)305-315
Number of pages11
JournalJournal of Cell Biology
Issue number2
StatePublished - Jul 21 2003


  • Membrane localization
  • Membrane trafficking
  • Phospholipase D
  • Phox homology domain
  • Pleckstrin homology domain

ASJC Scopus subject areas

  • Cell Biology


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