Phosphatidylinositol 4-phosphate 5-kinase alpha is a downstream effector of the small G protein ARF6 in membrane ruffle formation.
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.
Honda
A
A
Department of Biological Information, Tokyo Institute of Technology, Yokohama, Japan.
Nogami
M
M
Yokozeki
T
T
Yamazaki
M
M
Nakamura
H
H
Watanabe
H
H
Kawamoto
K
K
Nakayama
K
K
Morris
A J
AJ
Frohman
M A
MA
Kanaho
Y
Y
D020823:ADP-Ribosylation Factor 1 / Q000302:isolation & purification; D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000302:isolation & purification / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002417:Cattle; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000502:physiology*; D004789:Enzyme Activation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008969:Molecular Sequence Data; D010712:Phosphatidic Acids / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D000089982:ADP-Ribosylation Factor 6; D007527:Isoenzymes; D010712:Phosphatidic Acids; D019269:Phosphatidylinositol 4,5-Diphosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; C105606:phospholipase D2; D010739:Phospholipase D; D020823:ADP-Ribosylation Factor 1; D020727:ADP-Ribosylation Factors