Phosphatidylinositol 4-phosphate 5-kinase alpha is a downstream effector of the small G protein ARF6 in membrane ruffle formation

Cell. 1999 Nov 24;99(5):521-32. doi: 10.1016/s0092-8674(00)81540-8.


Synthesis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], a signaling phospholipid, is primarily carried out by phosphatidylinositol 4-phosphate 5-kinase [PI(4)P5K], which has been reported to be regulated by RhoA and Rac1. Unexpectedly, we find that the GTPgammaS-dependent activator of PI(4)P5Kalpha is the small G protein ADP-ribosylation factor (ARF) and that the activation strictly requires phosphatidic acid, the product of phospholipase D (PLD). In vivo, ARF6, but not ARF1 or ARF5, spatially coincides with PI(4)P5Kalpha. This colocalization occurs in ruffling membranes formed upon AIF4 and EGF stimulation and is blocked by dominant-negative ARF6. PLD2 similarly translocates to the ruffles, as does the PH domain of phospholipase Cdelta1, indicating locally elevated PI(4,5)P2. Thus, PI(4)P5Kalpha is a downstream effector of ARF6 and when ARF6 is activated by agonist stimulation, it triggers recruitment of a diverse but interactive set of signaling molecules into sites of active cytoskeletal and membrane rearrangement.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADP-Ribosylation Factor 1 / isolation & purification
  • ADP-Ribosylation Factors / isolation & purification
  • ADP-Ribosylation Factors / metabolism*
  • Amino Acid Sequence
  • Animals
  • Biological Transport
  • Cattle
  • Cell Compartmentation
  • Cell Membrane / physiology*
  • Enzyme Activation
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Isoenzymes / metabolism
  • Molecular Sequence Data
  • Phosphatidic Acids / metabolism
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Phospholipase D / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Sequence Homology, Amino Acid
  • Signal Transduction


  • Isoenzymes
  • Phosphatidic Acids
  • Phosphatidylinositol 4,5-Diphosphate
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Phosphotransferases (Alcohol Group Acceptor)
  • 1-phosphatidylinositol-4-phosphate 5-kinase
  • phospholipase D2
  • Phospholipase D
  • ADP-Ribosylation Factor 1
  • ADP-Ribosylation Factors
  • ADP-ribosylation factor 6