To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front

J Cell Biol. 2006 Jul 31;174(3):437-45. doi: 10.1083/jcb.200604113. Epub 2006 Jul 24.


Chemoattractants like f-Met-Leu-Phe (fMLP) induce neutrophils to polarize by triggering divergent signals that promote the formation of protrusive filamentous actin (F-actin; frontness) and RhoA-dependent actomyosin contraction (backness). Frontness locally inhibits backness and vice versa. In neutrophil-like HL60 cells, blocking phosphatidylinositol-3,4,5-tris-phosphate (PIP3) accumulation with selective inhibitors of PIP3 synthesis completely prevents fMLP from activating a PIP3-dependent kinase and Cdc42 but not from stimulating F-actin accumulation. PIP3-deficient cells show reduced fMLP-dependent Rac activity and unstable pseudopods, which is consistent with the established role of PIP3 as a mediator of positive feedback pathways that augment Rac activation at the front. Surprisingly, such cells also show reduced RhoA activation and RhoA-dependent contraction at the trailing edge, leading to the formation of multiple lateral pseudopods. Cdc42 mediates PIP3's positive effect on RhoA activity. Thus, PIP3 and Cdc42 maintain stable polarity with a single front and a single back not only by strengthening pseudopods but also, at longer range, by promoting RhoA-dependent actomyosin contraction at the trailing edge.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Differentiation / drug effects
  • Cell Polarity* / drug effects
  • Cells, Cultured
  • Chemotaxis, Leukocyte / drug effects
  • HL-60 Cells
  • Humans
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Neutrophils / cytology*
  • Phenotype
  • Phosphatidylinositol Phosphates / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Pseudopodia / drug effects
  • Signal Transduction*
  • Thiazoles / pharmacology
  • Thiazolidines
  • cdc42 GTP-Binding Protein / metabolism*
  • rhoA GTP-Binding Protein / metabolism*


  • Bridged Bicyclo Compounds, Heterocyclic
  • Phosphatidylinositol Phosphates
  • Phosphoinositide-3 Kinase Inhibitors
  • Thiazoles
  • Thiazolidines
  • phosphatidylinositol 3,4,5-triphosphate
  • N-Formylmethionine Leucyl-Phenylalanine
  • cdc42 GTP-Binding Protein
  • rhoA GTP-Binding Protein
  • latrunculin B