Phospholipase D signaling: orchestration by PIP2 and small GTPases

Naunyn Schmiedebergs Arch Pharmacol. 2007 Feb;374(5-6):399-411. doi: 10.1007/s00210-007-0131-4. Epub 2007 Jan 24.


Hydrolysis of phosphatidylcholine by phospholipase D (PLD) leads to the generation of the versatile lipid second messenger, phosphatidic acid (PA), which is involved in fundamental cellular processes, including membrane trafficking, actin cytoskeleton remodeling, cell proliferation and cell survival. PLD activity can be dramatically stimulated by a large number of cell surface receptors and is elaborately regulated by intracellular factors, including protein kinase C isoforms, small GTPases of the ARF, Rho and Ras families and, particularly, by the phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP(2)). PIP(2) is well known as substrate for the generation of second messengers by phospholipase C, but is now also understood to recruit and/or activate a variety of actin regulatory proteins, ion channels and other signaling proteins, including PLD, by direct interaction. The synthesis of PIP(2) by phosphoinositide 5-kinase (PIP5K) isoforms is tightly regulated by small GTPases and, interestingly, by PA as well, and the concerted formation of PIP(2) and PA has been shown to mediate receptor-regulated cellular events. This review highlights the regulation of PLD by membrane receptors, and describes how the close encounter of PLD and PIP5K isoforms with small GTPases permits the execution of specific cellular functions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biological Transport
  • Humans
  • Models, Biological
  • Monomeric GTP-Binding Proteins / metabolism*
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Phospholipase D / metabolism*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Signal Transduction*
  • rho GTP-Binding Proteins / metabolism


  • Phosphatidylinositol 4,5-Diphosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • Phospholipase D
  • Monomeric GTP-Binding Proteins
  • rho GTP-Binding Proteins