title: PIP₃-dependent macropinocytosis is incompatible with chemotaxis.
abstract: In eukaryotic chemotaxis, the mechanisms connecting external signals to the motile apparatus remain unclear. The role of the lipid phosphatidylinositol 3,4,5-trisphosphate (PIP₃) has been particularly controversial. PIP₃ has many cellular roles, notably in growth control and macropinocytosis as well as cell motility. Here we show that PIP₃ is not only unnecessary for Dictyostelium discoideum to migrate toward folate, but actively inhibits chemotaxis. We find that macropinosomes, but not pseudopods, in growing cells are dependent on PIP₃. PIP₃ patches in these cells show no directional bias, and overall only PIP₃-free pseudopods orient up-gradient. The pseudopod driver suppressor of cAR mutations (SCAR)/WASP and verprolin homologue (WAVE) is not recruited to the center of PIP₃ patches, just the edges, where it causes macropinosome formation. Wild-type cells, unlike the widely used axenic mutants, show little macropinocytosis and few large PIP₃ patches, but migrate more efficiently toward folate. Tellingly, folate chemotaxis in axenic cells is rescued by knocking out phosphatidylinositide 3-kinases (PI 3-kinases). Thus PIP₃ promotes macropinocytosis and interferes with pseudopod orientation during chemotaxis of growing cells.
authors.affiliation: Beatson Institute for Cancer Research, Glasgow G61 1BD, Scotland, UK.
authors.forename: Douwe M
authors.initials: DM
authors.lastname: Veltman
authors.forename: Michael G
authors.initials: MG
authors.lastname: Lemieux
authors.forename: David A
authors.initials: DA
authors.lastname: Knecht
authors.forename: Robert H
authors.initials: RH
authors.lastname: Insall
mesh_terms: D002465:Cell Movement / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D004023:Dictyostelium / Q000502:physiology*; D005492:Folic Acid / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010873:Pinocytosis / Q000502:physiology*; D015800:Protozoan Proteins / Q000235:genetics; D011554:Pseudopodia; D015398:Signal Transduction
chemical_list: D018129:Phosphatidylinositol Phosphates; D015800:Protozoan Proteins; C491975:SCAR protein, Dictyostelium; C060974:phosphatidylinositol 3,4,5-triphosphate; D005492:Folic Acid