Chemoattractant-induced phosphatidylinositol 3,4,5-trisphosphate accumulation is spatially amplified and adapts, independent of the actin cytoskeleton.
Experiments in amoebae and neutrophils have shown that local accumulations of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P(3)] mediate the ability of cells to migrate during gradient sensing. To define the nature of this response, we subjected Dictyostelium discoideum cells to measurable temporal and spatial chemotactic inputs and analyzed the accumulation of PI(3,4,5)P(3) on the membrane, as well as the recruitment of the enzymes phosphoinositide 3-kinase and PTEN. In latrunculin-treated cells, spatial gradients elicited a PI(3,4,5)P(3) response only on the front portion of the cell where the response increased more steeply than the gradient and did not depend on its absolute concentration. Phosphoinositide 3-kinase bound to the membrane only at the front, although it was less sharply localized than PI(3,4,5)P(3). Membrane-bound PTEN was highest at the rear and varied inversely with receptor occupancy. The localization of PI(3,4,5)P(3) was enhanced further in untreated polarized cells containing an intact cytoskeleton. Interestingly, the treated cells could respond to two independent gradients simultaneously, demonstrating that a response at the front does not necessarily inhibit the back. Combinations of temporal and spatial stimuli provided evidence of an inhibitory process and showed that a gradient generates a persistent steady-state response independent of a previous history of exposure to chemoattractant. These results support a local excitation/global inhibition model and argue against other schemes proposed to explain directional sensing.
Janetopoulos
Chris
C
Department of Cell Biology, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Ma
Lan
L
Devreotes
Peter N
PN
Iglesias
Pablo A
PA
D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002460:Cell Line; D016764:Cell Polarity; D002630:Chemotactic Factors / Q000378:metabolism / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004023:Dictyostelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005453:Fluorescence; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002630:Chemotactic Factors; D018129:Phosphatidylinositol Phosphates; D013844:Thiazoles; D053778:Thiazolidines; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; C037067:latrunculin A