Abstract
The crawling movement of cells in response to a chemoattractant gradient is a complex process requiring the coordination of various subcellular activities. Although a complete description of the mechanisms underlying cell movement remains elusive, the very first step of directional sensing, enabling the cell to perceive the imposed gradient, is becoming more transparent. A fundamental problem of directional sensing is its exquisite sensitivity. Even in the presence of relatively shallow chemoattractant gradients, cell projections are extended precisely in the region exposed to the highest chemoattractant concentration. This reflects the existence of a mechanism for amplifying the external signal. Recent experiments have identified a potential candidate for the seat of this amplification—membrane phosphoinositides such as PI4,5P2 and PI3,4,5P3 appear to be the first components of the signal transduction pathway to be amplified. Perturbing the cell with various chemoattractant gradients reveals a rich spectrum of phosphoinositide dynamics (Parent, C. A., and P. N. Devreotes. Science 284:765, 1999). The goal of this work is to develop a mathematical model of these phosphoinositide dynamics. Specifically, we address the following questions: (a) Which signaling pathway could lead to the localized accumulation of membrane phosphoinositides? (b) Why is this accumulation independent of the slope and mean value of the chemoattractant gradient? The model is based on the phosphoinositide cycle that transfers phosphoinositides between the plasma membrane and endoplasmic reticulum. We show that a mathematical model taking due account of receptor desensitization and the reaction-diffusion processes of the phosphoinositide cycle captures many of the experimentally observed dynamics. Having shown the plausibility of the model with respect to directional sensing, we discuss its implications for lamellipod extension, the process that follows directional sensing. © 2001 Biomedical Engineering Society.
PAC01: 8717Jj, 8717Aa
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References
Alberts, B., D. Bray, J. Lewis, M. Raff, K. Roberts, and J. D. Watson, Molecular Biology of the Cell, 3rd ed. New York: Garland, 1994.
Albritton, N. L., T. Meyer, and L. Stryer. Science258:1812, 1992.
Alon, U., M. G. Surette, N. Barkai, and S. Leibler. Nature (London)397:168, 1999.
Barkai, N.and S. Leibler. Nature (London)387:913, 1997.
Berridge, M. J.Nature (London)361:315, 1993.
Berridge, M. J., and R. F. Irvine. Nature (London)341:197, 1989.
Borisy, G. G.and T. M. Svitkina. Curr. Opin. Cell Biol.12:91, 2000.
Botelho, R. J., M. Teruel, R. Dierkman, R. Anderson, A. Wells, J. D. York, T. Meyer, and S. Grinstein. J. Cell Biol.151:1353, 2000.
Chahine, J. M. E. H., S. Cribier, and P. F. Devaux. Proc. Natl. Acad. Sci. U.S.A.90:447, 1993.
Coates, T., R. Watts, R. Hartman, and T. Howard. J. Cell Biol.117:765, 1992.
Cockcroft, S.Chem. Phys. Lipids98:23, 1999.
Devreotes, P. N.and J. A. Sherring. J. Biol. Chem.260:6378, 1985.
Eddy, R. J., L. M. Pierini, F. Matsumura, and F. R. Maxfield. J. Cell. Sci.113:1287, 2000.
Firtel, R. A.and C. Y. Chung. BioEssays22:603, 2000.
Fruman, D. A., R. E. Meyers, and L. C. Cantley. Annu. Rev. Biochem.67:481, 1998.
Gierer, A.and H. Meinhardt. Kybernetik12:30, 1972.
Haugh, J. M., F. Codazzi, M. Teruel, and T. Meyer. J. Cell Biol.151:1269, 2000.
Haugh, J. M., A. Wells, and D. A. Lauffenburger. Biotechnol. Bioeng.70:225, 2000.
Helmkamp, G. M., In: Intracellular Transfer of Lipid Molecules, Subcellular Biochemistry Vol. 16, edited by H. J. Hilderson. (New York, Plenum, 1990), Chap. 6, pp. 129–174.
Hinchliffe, K.Curr. Biol.10:R104, 2000.
Honda, A., M. Nogami, T. Yokozeki, M. Yamazaki, H. Nakamura, H. Watanabe, K. Kawamoto, K. Nakayama, A. J. Morris, M. A. Frohman, and Y. Kanaho. Cell99:521, 1999.
Janmey, P. A.Annu. Rev. Physiol.56:169, 1994.
Jin, T., N. Zhang, Y. Long, C. A. Parent, and P. N. Devreotes. Science287:1034, 2000.
Kerner, B. S., and V. V. Osipov. Autosolitons: A New Approach to Problems of Self-Organization and Turbulence, 1st ed. Dordrecht, Kluwer, 1994.
Kjöller, L.and A. Hall. Exp. Cell Res.253:166, 1999.
Lauffenburger, D. A.and A. F. Horwitz. Cell84:359, 1996.
Lauffenburger, D. A., and J. J. Linderman. Receptors: Models for Binding, Trafficking and Signaling, 1st ed. New York, Oxford University Press, 1993.
Lawson, M. A.and F. R. Maxfield. Nature (London)377:75, 1995.
Lemmon, M. A., M. Falasca, K. M. Ferguson, and J. Schlessinger. Trends Cell Biol.7:237, 1997.
Marks, P. W.and F. R. Maxfield. J. Cell Biol.110:43, 1990.
Meili, R., C. Ellsworth, S. Lee, T. B. K. Reddy, H. Ma, and R. A. Firtel. EMBO J.112:2867, 1999.
Meinhardt, H.J. Cell. Sci.112:2867, 1999.
Monaco, M. E.and J. R. Adelson. Biochem. J.279:337, 1991.
Moritz, A., P. N. E. Graan, W. H. Gispen, and K. W. A. Wirtz. J. Biol. Chem.267:7207, 1992.
Mullins, R. D.Curr. Opin. Cell Biol.12:91, 2000.
NAG Fortran Library Introductory Guide, Mark 18, Oxford, UK: Numerical Algorithms Group, 1999.
Parent, C. A.and P. N. Devreotes. Science284:765, 1999.
Parent, C. A., B. J. Blacklock, W. M. Froelich, D. B. Murphy, and P. N. Devreotes. Cell95:81, 1998.
Servant, G., O. D. Weiner, E. R. Neptune, J. W. Sedat, and H. R. Bourne. Mol. Biol. Cell10:1163, 1999.
Servant, G., O. D. Weiner, P. Herzmark, T. Balla, J. W. Sedat, and H. R. Bourne. Science287:1037, 2000.
Tall, E. G., I. Spector, S. N. Pentyala, I. Bitter, and M. J. Rebecchi. Curr. Biol.10:743, 2000.
Tranquillo, R. T., D. A. Lauffenburger, and S. H. Zigmond. J. Cell Biol.106:303, 1988.
Tolias, K. F.et al.Curr. Biol.10:153, 2000.
Várnai, P.and T. Balla. J. Cell Biol.143:501, 1998.
Willars, G. B., S. R. Nahorski, and R. A. J. Challiss. J. Biol. Chem.273:5037, 1998.
Xiao, Z., N. Zhang, D. B. Murphy, and P. N. Devreotes. J. Cell Biol.139:365, 1997.
Zigmond, S. H.J. Cell Biol.150:F117, 2000.
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Narang, A., Subramanian, K.K. & Lauffenburger, D.A. A Mathematical Model for Chemoattractant Gradient Sensing Based on Receptor-Regulated Membrane Phospholipid Signaling Dynamics. Annals of Biomedical Engineering 29, 677–691 (2001). https://doi.org/10.1114/1.1385805
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DOI: https://doi.org/10.1114/1.1385805