Exogenous phospholipase D generates lysophosphatidic acid and activates Ras, Rho and Ca2+ signaling pathways

Curr Biol. 1998 Mar 26;8(7):386-92. doi: 10.1016/s0960-9822(98)70157-5.


Background: Phospholipase D (PLD) hydrolyzes phospholipids to generate phosphatidic acid (PA) and a free headgroup. PLDs occur as both intracellular and secreted forms; the latter can act as potent virulence factors. Exogenous PLD has growth-factor-like properties, in that it induces proto-oncogene transcription, mitogenesis and cytoskeletal changes in target cells. The underlying mechanism is unknown, although it is generally assumed that PLD action is mediated by PA serving as a putative second messenger.

Results: In quiescent fibroblasts, exogenous PLD (from Streptomyces chromofuscus) stimulated accumulation of the GTP-bound form of Ras, activation of mitogen-activated protein (MAP) kinase and DNA synthesis, through the pertussis-toxin-sensitive inhibitory G protein Gi. Furthermore, PLD mimicked bioactive lysophospholipids (but not PA) in inducing Ca2+ mobilization, membrane depolarization and Rho-mediated neurite retraction. PLD action was mediated by Iysophosphatidic acid (LPA) derived from Iysophosphatidylcholine acting on cognate G-protein-coupled LPA receptor(s). There was no evidence for the involvement of PA in mediating the effects of exogenous PLD.

Conclusions: Our results provide a molecular explanation for the multiple cellular responses to exogenous PLDs. These PLDs generate bioactive LPA from pre-existing Iysophosphatidylcholine in the outer membrane leaflet, resulting in activation of G-protein-coupled LPA receptors and consequent activation of Ras, Rho and Ca2+ signaling pathways. Unscheduled activation of LPA receptors may underlie, at least in part, the known pathogenic effects of exogenous PLDs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cell Line
  • Cytoskeleton / drug effects
  • GTP-Binding Proteins / metabolism*
  • Lysophosphatidylcholines / metabolism
  • Lysophosphatidylcholines / pharmacology
  • Lysophospholipids / biosynthesis*
  • Membrane Proteins / metabolism*
  • Phospholipase D / metabolism
  • Phospholipase D / pharmacology*
  • Rats
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled*
  • Receptors, Lysophosphatidic Acid
  • Signal Transduction / drug effects
  • ras Proteins / metabolism*
  • rhoB GTP-Binding Protein


  • Lysophosphatidylcholines
  • Lysophospholipids
  • Membrane Proteins
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Receptors, Lysophosphatidic Acid
  • Phospholipase D
  • GTP-Binding Proteins
  • ras Proteins
  • rhoB GTP-Binding Protein
  • Calcium