Two complementary, local excitation, global inhibition mechanisms acting in parallel can explain the chemoattractant-induced regulation of PI(3,4,5)P3 response in dictyostelium cells.
Chemotaxing cells, such as Dictyostelium and mammalian neutrophils, sense shallow chemoattractant gradients and respond with highly polarized changes in cell morphology and motility. Uniform chemoattractant stimulation induces the transient translocations of several downstream signaling components, including phosphoinositide 3-kinase (PI3K), tensin homology protein (PTEN), and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). In contrast, static spatial chemoattractant gradients elicit the persistent, amplified localization of these molecules. We have proposed a model in which the response to chemoattractant is regulated by a balance of a local excitation and a global inhibition, both of which are controlled by receptor occupancy. This model can account for both the transient and spatial responses to chemoattractants, but alone does not amplify the external gradient. In this article, we develop a model in which parallel local excitation, global inhibition mechanisms control the membrane binding of PI3K and PTEN. Together, the action of these enzymes induces an amplified PI(3,4,5)P3 response that agrees quantitatively with experimentally obtained plekstrin homology-green fluorescent protein distributions in latrunculin-treated cells. We compare the model's performance with that of several mutants in which one or both of the enzymes are disrupted. The model accounts for the observed response to multiple, simultaneous chemoattractant cues and can recreate the cellular response to combinations of temporal and spatial stimuli. Finally, we use the model to predict the response of a cell where only a fraction is stimulated by a saturating dose of chemoattractant.
Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.
Lan
L
Ma
Chris
C
Janetopoulos
Liu
L
Yang
Peter N
PN
Devreotes
Pablo A
PA
Iglesias
D000818:Animals; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D003198:Computer Simulation; D000242:Cyclic AMP / Q000494:pharmacology; D004023:Dictyostelium / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors; D008954:Models, Biological; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D000242:Cyclic AMP; D004791:Enzyme Inhibitors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols; D010744:Phosphoric Monoester Hydrolases; D025521:Tumor Suppressor Proteins; C112403:PIP3-APB