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Spatial regulation of PI3K signaling during chemotaxis

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Abstract Phosphoinositide 3‐kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3′ OH position of the inositol ring of phosphoinositides on the inner leaf of the plasma membrane. Receptor‐mediated activation of the PI3K pathway plays a crucial role in numerous signaling pathways and regulates a number of critical cellular processes, including growth, differentiation, survival and directed migration. In this focus article, we review the temporal and spatial regulation of PI3K in chemotaxing cells with particular emphasis on the amoeba Dictyostelium as well as neutrophils. We also briefly discuss one model used to elucidate the PI3K pathway. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models

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Local‐excitation, global‐inhibition model for gradient sensing. In this mechanism, chemoattractant receptor occupancy triggers a fast local (possibly membrane bound) excitatory signal, and a slower, global (possibly cytosolic) response. The balance in their activities produces the cellular response. When stimulated in a spatially uniform manner, the fast excitation causes a transient response that is extinguished when the inhibitor catches up. A gradient induces increased excitation at the front and inhibition at the rear, leading to a graded response.

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Response of cells to spatial and temporal combinations of stimuli. Cells originally in a gradient were stimulated by a large, transient stimulus. The initial bolus dissipated and the stable gradient was reestablished. The initial spatial response to the gradient was replaced by a uniform translocation of PH‐GFP. After removal of the stimulus, the PH‐GFP response disappeared transiently everywhere, even in the presence of the gradient, before eventually being reestablished. As shown here, the computational model recreates the responses observed experimentally. (Simulation results are reprinted with permission from Ref 18. Copyright 2004 the Biophysical Society; Dictyostelium images are reprinted with permission from Ref 15. Copyright 2004 National Academy of Sciences, USA).

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Simulation of gradient sensing. (a) Micropipette containing cy3‐cAMP (red) is placed near a latrunculin‐treated Dictyostelium cell expressing PH‐GFP. This marker translocates selectively toward the membrane closest to the pipette. Scale bar is 10 µm. (b–e) Simulation results, showing cAMP (b), PI3K (c), PTEN (d), and PI(3,4,5)P3 (e) along the 2‐dimensional model of the 14 µm diameter cell. (f) Spatial amplification can be seen by plotting the intensity levels as a function of angle along the membrane. The ‘zero’ angle points toward the micropipette. Experimental intensities for the cell in panel A (small red circles for cy3‐cAMP, small green squares for PH‐GFP), as well as simulation values. All data sets have been normalized to their respective maxima. (Reprinted with permission from Ref 18. Copyright 2004 the Biophysical Society).

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(a) Model in which complementary LEGI mechanisms (each with excitation and inhibition elements) regulating PI3K and PTEN binding sites (PI3K‐BS and PTEN‐BS) lead to amplified production of PI(3,4,5)P3. (b) Virtual cell implementation of the model. Each species, together with its localization, is represented by the dark shaded circle. The solid lines indicate the inputs and outputs of the reactions, represented by the light shaded ovals. Catalytic activities are represented by dashed lines. (Reprinted with permission from Ref 18. Copyright 2004 the Biophysical Society).

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