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Spatial organization of intracellular communication: insights from imaging

Key Points

  • Biological structures that generate function can arise from fluctuations and local interactions of proteins by self-organization. To understand how these patterns can emerge, measurements of protein mobility and activity need to be combined.

  • Signalling networks often include reaction cycles, which can dynamically maintain a limited number of activity states. Such discrete network states can define key aspects of contrasting cellular behaviours.

  • Reaction cycles, which occur around preformed cellular templates, such as chromatin in mitosis, can spatially constrain signals by reaction–diffusion and thereby guide the formation of structures during cellular morphogenesis.

  • Supramolecular structures, such as the mitotic spindle, emerge from a complex interplay between a limited set of preformed templates and de novo structure formation by self-organization.

  • Concepts that describe the organization of insect colonies, such as the self-organized growth of a structure based on information gathered from work-in-progress (stigmergy), can provide useful analogies to cellular organization.

  • To understand intracellular communication and cellular organization, a recursive feedback loop between microscopic imaging and modelling will give us deeper insight into how the collective behaviour of nanometre-sized molecules generates functional structures on the micrometre scale of cells.

Abstract

Signal transduction is the transfer of information about the compositional state of the extracellular environment to the intracellular cytoplasm that elicits a morphological or genetic response. In more general terms, this can also be the communication of the state of supramolecular structures, such as the plasma membrane or chromatin, in the cell. This information is relayed through space by the cytoplasm and is mediated by transitions between the steady states of the cytoplasm's reaction networks. To uncover the principles that underlie the generation of spatiotemporal patterns of activity which guide cellular behaviour, functional imaging techniques that report on the activity of molecules must be combined with imaging techniques that report on the mobility of molecules.

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Figure 1: Comparison of macroscopic and microscopic self-organization.
Figure 2: Measurement of protein mobility in cells.
Figure 3: Measurement of protein reactions in cells.
Figure 4: Kinase–phosphatase reaction cycles.
Figure 5: Gradients generate local cytoplasmic states, which steer morphological processes.
Figure 6: Self-organization in intracellular pattern formation and structural growth processes.

References

  1. 1

    Nicolis, G. & Prigogine Ilya. Self-organization in Nonequilibrum Systems: From Dissipative Structures to Order Through Fluctuations (Wiley, New York, 1977).

    Google Scholar 

  2. 2

    Grasse, P. P. La reconstruction du nid et les coordinations inter-individuelles chez Bellicositermes natalensis et Cubitermes sp. La theorie de la stigmergie: Essai d'interpretation du comportement des termites constructeurs. Insectes Sociaux 6, 41–81 (1959) (in French).

    Google Scholar 

  3. 3

    Bruinsma, O. H. An Analysis of Building Behaviour of the Termite Macrotermes subhyalinus (Rambur). Thesis, Wageningen Univ. (1979).

    Google Scholar 

  4. 4

    Camazine, S. et al. Self-Organization in Biological Systems (eds Anderson, P. W., Epstein, J. M., Foley, D. K., Levin, S. A. & Nowak, M. A.) (Princeton Univeristy Press, Princeton, 2001). A detailed and insightful overview about general concepts for organization and pattern formation in macroscopic biological systems.

    Google Scholar 

  5. 5

    Bouzigues, C., Morel, M., Triller, A. & Dahan, M. Asymmetric redistribution of GABA receptors during GABA gradient sensing by nerve growth cones analysed by single quantum dot imaging. Proc. Natl Acad. Sci. USA 104, 11251–11256 (2007). An elegant study combining imaging and modelling to reveal positive feedback regulation in GABA signalling, centred around random fluctuations of dynamic microtubules.

    CAS  PubMed  Google Scholar 

  6. 6

    Mitchison, T. & Kirschner, M. Dynamic instability of microtubule growth. Nature 312, 237–242 (1984).

    CAS  Google Scholar 

  7. 7

    Kalab, P., Weis, K. & Heald, R. Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts. Science 295, 2452–2456 (2002).

    CAS  Google Scholar 

  8. 8

    Bastiaens, P., Caudron, M., Niethammer, P. & Karsenti, E. Gradients in the self-organization of the mitotic spindle. Trends Cell Biol. 16, 125–134 (2006).

    CAS  PubMed  Google Scholar 

  9. 9

    Caudron, M., Bunt, G., Bastiaens, P. & Karsenti, E. Spatial coordination of spindle assembly by chromosome-mediated signalling gradients. Science 309, 1373–1376 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Einstein, A. The motion of elements suspended in static liquids as claimed in the molecular kinetic theory of heat. Ann. Phys. 17, 549–560 (1905).

    CAS  Google Scholar 

  11. 11

    Axelrod, D., Koppel, D. E., Schlessinger, J., Elson, E. & Webb, W. W. Mobility measurement by analysis of fluorescence photobleaching recovery kinetics. Biophys. J. 16, 1055–1069 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Dunn, G. A., Dobbie, I. M., Monypenny, J., Holt, M. R. & Zicha, D. Fluorescence localization after photobleaching (FLAP): a new method for studying protein dynamics in living cells. J. Microsc. 205, 109–112 (2002).

    CAS  PubMed  Google Scholar 

  13. 13

    Patterson, G. H. & Lippincott-Schwartz, J. A photoactivatable GFP for selective photolabelling of proteins and cells. Science 297, 1873–1877 (2002).

    CAS  Google Scholar 

  14. 14

    Ando, R., Hama, H., Yamamoto-Hino, M., Mizuno, H. & Miyawaki, A. An optical marker based on the UV-induced green-to-red photoconversion of a fluorescent protein. Proc. Natl Acad. Sci. USA 99, 12651–12656 (2002).

    CAS  Google Scholar 

  15. 15

    Gurskaya, N. G. et al. Engineering of a monomeric green-to-red photoactivatable fluorescent protein induced by blue light. Nature Biotech. 24, 461–465 (2006).

    CAS  Google Scholar 

  16. 16

    Rocks, O. et al. The palmitoylation machinery is a spatially organizing system for peripheral membrane proteins. Cell 141, 458–471 (2010).

    CAS  Google Scholar 

  17. 17

    Giordano, L., Jovin, T. M., Irie, M. & Jares-Erijman, E. A. Diheteroarylethenes as thermally stable photoswitchable acceptors in photochromic fluorescence resonance energy transfer (pcFRET). J. Am. Chem. Soc. 124, 7481–7489 (2002).

    CAS  PubMed  Google Scholar 

  18. 18

    Ando, R., Mizuno, H. & Miyawaki, A. Regulated fast nucleocytoplasmic shuttling observed by reversible protein highlighting. Science 306, 1370–1373 (2004). Powerful ensemble measurements of protein mobility using the novel fluorescent protein Dronpa, which allowed reversible highlighting and therefore repeated mobility measurements in an individual cell during growth factor stimulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Koppel, D. E. & Sheetz, M. P. A localized pattern photobleaching method for the concurrent analysis of rapid and slow diffusion processes. Biophys. J. 43, 175–181 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Kang, M., Day, C. A., Drake, K., Kenworthy, A. K. & DiBenedetto, E. A generalization of theory for two-dimensional fluorescence recovery after photobleaching applicable to confocal laser scanning microscopes. Biophys. J. 97, 1501–1511 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Gelles, J., Schnapp, B. J. & Sheetz, M. P. Tracking kinesin-driven movements with nanometre-scale precision. Nature 331, 450–453 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Anderson, C. M., Georgiou, G. N., Morrison, I. E., Stevenson, G. V. & Cherry, R. J. Tracking of cell surface receptors by fluorescence digital imaging microscopy using a charge-coupled device camera. Low-density lipoprotein and influenza virus receptor mobility at 4°C. J. Cell Sci. 101, 415–425 (1992).

    PubMed  Google Scholar 

  23. 23

    Ghosh, R. N. & Webb, W. W. Automated detection and tracking of individual and clustered cell surface low density lipoprotein receptor molecules. Biophys. J. 66, 1301–1318 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Dahan, M. et al. Diffusion dynamics of glycine receptors revealed by single-quantum dot tracking. Science 302, 442–445 (2003).

    CAS  PubMed  Google Scholar 

  25. 25

    Manley, S. et al. High-density mapping of single-molecule trajectories with photoactivated localization microscopy. Nature Methods 5, 155–157 (2008). Photoswitchable dyes allowed high-density mapping of protein diffusion at subdiffraction resolution.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Suzuki, K., Ritchie, K., Kajikawa, E., Fujiwara, T. & Kusumi, A. Rapid hop diffusion of a G-protein-coupled receptor in the plasma membrane as revealed by single-molecule techniques. Biophys. J. 88, 3659–3680 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Saxton, M. J. A biological interpretation of transient anomalous subdiffusion. I. Qualitative model. Biophys. J. 92, 1178–1191 (2007).

    CAS  PubMed  Google Scholar 

  28. 28

    Ram, S., Prabhat, P., Chao, J., Ward, E. S. & Ober, R. J. High accuracy 3D quantum dot tracking with multifocal plane microscopy for the study of fast intracellular dynamics in live cells. Biophys. J. 95, 6025–43 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Han, K. Y. et al. Three-dimensional stimulated emission depletion microscopy of nitrogen-vacancy centers in diamond using continuous-wave light. Nano Lett. 9, 3323–3329 (2009).

    CAS  PubMed  Google Scholar 

  30. 30

    Batalov, A. et al. Low temperature studies of the excited-state structure of negatively charged nitrogen-vacancy colour centers in diamond. Phys. Rev. Lett. 102, 195506 (2009).

    CAS  PubMed  Google Scholar 

  31. 31

    Magde, D., Elson, E., Webb, W. W. Thermodynamic fluctuations in a reacting system—measurement by fluorescence correlation spectroscopy. Phys. Rev. Lett. 29, 705–708 (1972).

    CAS  Google Scholar 

  32. 32

    Schwille, P., Haupts, U., Maiti, S. & Webb, W. W. Molecular dynamics in living cells observed by fluorescence correlation spectroscopy with one- and two-photon excitation. Biophys. J. 77, 2251–2265 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Hebert, B., Costantino, S. & Wiseman, P. W. Spatiotemporal image correlation spectroscopy (STICS) theory, verification, and application to protein velocity mapping in living CHO cells. Biophys. J. 88, 3601–3614 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Digman, M. A. et al. Fluctuation correlation spectroscopy with a laser-scanning microscope: exploiting the hidden time structure. Biophys. J. 88, L33–L36 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Danuser, G. & Waterman-Storer, C. M. Quantitative fluorescent speckle microscopy of cytoskeleton dynamics. Annu. Rev. Biophys. Biomol. Struct. 35, 361–387 (2006). A detailed review on quantitative speckle microscopy, discussing advantages and limits of FSM versus single molecule tracking and discussing several applications in studying cytoskeletal organization.

    CAS  Google Scholar 

  36. 36

    Waterman-Storer, C. M., Desai, A., Bulinski, J. C. & Salmon, E. D. Fluorescent speckle microscopy, a method to visualize the dynamics of protein assemblies in living cells. Curr. Biol. 8, 1227–1230 (1998).

    CAS  Google Scholar 

  37. 37

    Watanabe, N. & Mitchison, T. J. Single-molecule speckle analysis of actin filament turnover in lamellipodia. Science 295, 1083–1086 (2002). Single green fluorescent protein-labelled actin molecules were analysed by speckle microscopy in living cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Grecco, H. E. &. Bastiaens, P. I. H. in Live Cell Imaging: a Laboratory Manual (eds Goldman R. D. et al.) (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2010).

    Google Scholar 

  39. 39

    Förster, T. Zwischenmolekulare Energiewanderung und Fluoreszenz. Ann. Phys. 437, 55–75 (1948) (in German).

    Google Scholar 

  40. 40

    Gordon, G. W., Berry, G., Liang, X. H., Levine, B. & Herman, B. Quantitative fluorescence resonance energy transfer measurements using fluorescence microscopy. Biophys. J. 74, 2702–2713 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Mahajan, N. P., Harrison-Shostak, D. C., Michaux, J. & Herman, B. Novel mutant green fluorescent protein protease substrates reveal the activation of specific caspases during apoptosis. Chem. Biol. 6, 401–409 (1999).

    CAS  PubMed  Google Scholar 

  42. 42

    Bastiaens, P. I., Majoul, I. V., Verveer, P. J., Soling, H. D. & Jovin, T. M. Imaging the intracellular trafficking and state of the AB5 quaternary structure of cholera toxin. EMBO J. 15, 4246–4253 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Lakowicz, J. R., Szmacinski, H., Nowaczyk, K. & Johnson, M. L. Fluorescence lifetime imaging of free and protein-bound NADH. Proc. Natl Acad. Sci. USA 89, 1271–1275 (1992).

    CAS  PubMed  Google Scholar 

  44. 44

    Gadella, T. W. Jr & Jovin, T. M. Oligomerization of epidermal growth factor receptors on A431 cells studied by time-resolved fluorescence imaging microscopy. A stereochemical model for tyrosine kinase receptor activation. J. Cell Biol. 129, 1543–1558 (1995).

    CAS  PubMed  Google Scholar 

  45. 45

    Verveer, P. J., Squire, A. & Bastiaens, P. I. Global analysis of fluorescence lifetime imaging microscopy data. Biophys. J. 78, 2127–2137 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Verveer, P. J., Wouters, F. S., Reynolds, A. R. & Bastiaens, P. I. Quantitative imaging of lateral ErbB1 receptor signal propagation in the plasma membrane. Science 290, 1567–1570 (2000).

    CAS  PubMed  Google Scholar 

  47. 47

    Adams, S. R., Harootunian, A. T., Buechler, Y. J., Taylor, S. S. & Tsien, R. Y. Fluorescence ratio imaging of cyclic AMP in single cells. Nature 349, 694–697 (1991).

    CAS  PubMed  Google Scholar 

  48. 48

    Itoh, R. E. et al. Activation of Rac and Cdc42 video imaged by fluorescent resonance energy transfer-based single-molecule probes in the membrane of living cells. Mol. Cell. Biol. 22, 6582–6591 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Offterdinger, M., Georget, V., Girod, A. & Bastiaens, P. I. Imaging phosphorylation dynamics of the epidermal growth factor receptor. J. Biol. Chem. 279, 36972–36981 (2004).

    CAS  PubMed  Google Scholar 

  50. 50

    Mochizuki, N. et al. Spatio-temporal images of growth-factor-induced activation of Ras and Rap1. Nature 411, 1065–1068 (2001).

    CAS  PubMed  Google Scholar 

  51. 51

    Pertz, O., Hodgson, L., Klemke, R. L. & Hahn, K. M. Spatiotemporal dynamics of RhoA activity in migrating cells. Nature 440, 1069–1072 (2006).

    CAS  PubMed  Google Scholar 

  52. 52

    Niethammer, P., Bastiaens, P. & Karsenti, E. Stathmin-tubulin interaction gradients in motile and mitotic cells. Science 303, 1862–1866 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Hahn, K., DeBiasio, R. & Taylor, D. L. Patterns of elevated free calcium and calmodulin activation in living cells. Nature 359, 736–738 (1992).

    CAS  Google Scholar 

  54. 54

    Nalbant, P., Hodgson, L., Kraynov, V., Toutchkine, A. & Hahn, K. M. Activation of endogenous Cdc42 visualized in living cells. Science 305, 1615–1619 (2004).

    CAS  Google Scholar 

  55. 55

    Machacek, M. et al. Coordination of Rho GTPase activities during cell protrusion. Nature 461, 99–103 (2009). A combination of two biosensor concepts and computationally assisted correlation based on cellular protrusion dynamics enabled the comparative analysis of activation dynamics of three Rho GTPases.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Baird, G. S., Zacharias, D. A. & Tsien, R. Y. Circular permutation and receptor insertion within green fluorescent proteins. Proc. Natl Acad. Sci. USA 96, 11241–11246 (1999).

    CAS  PubMed  Google Scholar 

  57. 57

    Belousov, V. V. et al. Genetically encoded fluorescent indicator for intracellular hydrogen peroxide. Nature Methods 3, 281–286 (2006).

    CAS  Google Scholar 

  58. 58

    Berg, J., Hung., Y. P. & Yellen, G. A genetically encoded fluorescent reporter of ATP:ADP ratio. Nature Methods 6, 161–166 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Parent, C. A., Blacklock, B. J., Froehlich, W. M., Murphy, D. B. & Devreotes, P. N. G protein signalling events are activated at the leading edge of chemotactic cells. Cell 95, 81–91 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Meili, R. et al. Chemoattractant-mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium. EMBO J. 18, 2092–2105 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Servant, G. et al. Polarization of chemoattractant receptor signalling during neutrophil chemotaxis. Science 287, 1037–1040 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Ting, A. Y., Kain, K. H., Klemke, R. L. & Tsien, R. Y. Genetically encoded fluorescent reporters of protein tyrosine kinase activities in living cells. Proc. Natl Acad. Sci. USA 98, 15003–15008 (2001).

    CAS  PubMed  Google Scholar 

  63. 63

    Violin, J. D., Zhang, J., Tsien, R. Y. & Newton, A. C. A genetically encoded fluorescent reporter reveals oscillatory phosphorylation by protein kinase C. J. Cell Biol. 161, 899–909 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Xu, X. et al. Detection of programmed cell death using fluorescence energy transfer. Nucleic Acids Res. 26, 2034–2035 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Harpur, A. G., Wouters, F. S. & Bastiaens, P. I. Imaging FRET between spectrally similar GFP molecules in single cells. Nature Biotech. 19, 167–169 (2001).

    CAS  Google Scholar 

  66. 66

    Wichmann, O., Wittbrodt, J. & Schultz, C. A small-molecule FRET probe to monitor phospholipase A2 activity in cells and organisms. Angew. Chem. Int. Ed Engl. 45, 508–512 (2006).

    CAS  PubMed  Google Scholar 

  67. 67

    Yudushkin, I. A. et al. Live-cell imaging of enzyme-substrate interaction reveals spatial regulation of PTP1B. Science 315, 115–119 (2007). Direct observation of enzyme–substrate complexes by FLIM measurements of FRET allow spatial mapping of enzyme kinetic parameters in cells.

    CAS  PubMed  Google Scholar 

  68. 68

    Tyson, J. J., Chen, K. C. & Novak, B. Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signalling pathways in the cell. Curr. Opin. Cell Biol. 15, 221–231 (2003). A detailed review discussing how the topology of signal networks influences their response to inputs.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Ferrell, J. E. Jr. Tripping the switch fantastic: how a protein kinase cascade can convert graded inputs into switch-like outputs. Trends Biochem. Sci. 21, 460–466 (1996).

    CAS  PubMed  Google Scholar 

  70. 70

    Ferrell, J. E., Jr. & Machleder, E. M. The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. Science 280, 895–898 (1998).

    CAS  PubMed  Google Scholar 

  71. 71

    Kholodenko, B. N. Cell-signalling dynamics in time and space. Nature Rev. Mol. Cell Biol. 7, 165–176 (2006).

    CAS  Google Scholar 

  72. 72

    Santos, S. D. M., Verveer, P. J. & Bastiaens, P. I. H. Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nature Cell Biol. 9, 324–330 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Murphy, L. O., Smith, S., Chen, R. H., Fingar, D. C. & Blenis, J. Molecular interpretation of ERK signal duration by immediate early gene products. Nature Cell Biol. 4, 556–564 (2002).

    CAS  PubMed  Google Scholar 

  74. 74

    Laslo, P. et al. Multilineage transcriptional priming and determination of alternate haematopoietic cell fates. Cell 126, 755–766 (2006).

    CAS  PubMed  Google Scholar 

  75. 75

    Xiong, W. & Ferrell, J. E. Jr. A positive-feedback-based bistable 'memory module' that governs a cell fate decision. Nature 426, 460–465 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Ingolia, N. T. Topology and robustness in the Drosophila segment polarity network. PLoS Biol. 2, 805–815 (2004).

    CAS  Google Scholar 

  77. 77

    Niethammer, P. et al. Discrete states of a protein interaction network govern interphase and mitotic microtubule dynamics. PLoS Biol. 5, 190–202 (2007).

    CAS  Google Scholar 

  78. 78

    Brown, G. C. & Kholodenko, B. N. Spatial gradients of cellular phospho-proteins. FEBS Lett. 457, 452–454 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Hyman, A. A. & Karsenti, E. Morphogenetic properties of microtubules and mitotic spindle assembly. Cell 84, 401–410 (1996). The first discussion of the existence of intracellular activity gradients that have a role in spindle morphogenesis.

    CAS  Google Scholar 

  80. 80

    Kalab, P., Pralle, A., Isacoff, E. Y., Heald, R. & Weis, K. Analysis of a RanGTP-regulated gradient in mitotic somatic cells. Nature 440, 697–701 (2006).

    CAS  Google Scholar 

  81. 81

    Wollman, R. et al. Efficient chromosome capture requires a bias in the 'search-and-capture' process during mitotic-spindle assembly. Curr. Biol. 15, 828–832 (2005).

    CAS  Google Scholar 

  82. 82

    Andersen, S. S. et al. Mitotic chromatin regulates phosphorylation of stathmin/OP18. Nature 389, 640–643 (1997).

    CAS  Google Scholar 

  83. 83

    Tournebize, R. et al. Distinct roles of PP1 and PP2A-like phosphatases in control of microtubule dynamics during mitosis. EMBO J. 16, 5537–5549 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Fuller, B. G. et al. Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient. Nature 453, 1132–1136 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Maeder, C. I. et al. Spatial regulation of Fus3 MAP kinase activity through a reaction-diffusion mechanism in yeast pheromone signalling. Nature Cell Biol. 9, 1319–1326 (2007).

    CAS  PubMed  Google Scholar 

  86. 86

    Moseley, J. B., Mayeux, A., Paoletti, A. & Nurse, P. A spatial gradient coordinates cell size and mitotic entry in fission yeast. Nature 459, 857–860 (2009).

    CAS  PubMed  Google Scholar 

  87. 87

    Coppey, M., Boettiger, A. N., Berezhkovskii, A. M. & Shvartsman, S. Y. Nuclear trapping shapes the terminal gradient in the Drosophila embryo. Curr. Biol. 18, 915–919 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Pollard, T. D. & Borisy, G. G. Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453–465 (2003).

    CAS  Google Scholar 

  89. 89

    Walczak, C. E. & Heald, R. Mechanisms of mitotic spindle assembly and function. Int. Rev. Cytol. 265, 111–158 (2008).

    CAS  Google Scholar 

  90. 90

    Karsenti, E. Self-organization in cell biology: a brief history. Nature Rev. Mol. Cell Biol. 9, 255–262 (2008). An insightful article about the history of the concepts of intracellular self-organization.

    CAS  Google Scholar 

  91. 91

    Kikkawa, M., Ishikawa, T., Wakabayashi, T. & Hirokawa, N. Three-dimensional structure of the kinesin head-microtubule complex. Nature 376, 274–277 (1995).

    CAS  PubMed  Google Scholar 

  92. 92

    Hirose, K., Lockhart, A., Cross, R. A. & Amos, L. A. Three-dimensional cryoelectron microscopy of dimeric kinesin and ncd motor domains on microtubules. Proc. Natl Acad. Sci. USA 93, 9539–9544 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Turing, A. M. The chemical basis of morphogenesis. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 237, 37–72 (1952).

    Google Scholar 

  94. 94

    Nagorcka, B. N. Wavelike isomorphic prepatterns in development. J. Theor. Biol. 137, 127–162 (1989).

    CAS  PubMed  Google Scholar 

  95. 95

    Murray, J. D. A pre-pattern formation mechanism for animal coat markings. J. Theor. Biol. 88, 161–199 (1981).

    Google Scholar 

  96. 96

    A. G. Searle. Comparative Genetics of Coat Colour in Mammals. (Logos Press, London; Academic Press, New York, 1968).

    Google Scholar 

  97. 97

    Keilhack, H. et al. Phosphotyrosine 1173 mediates binding of the protein-tyrosine phosphatase SHP-1 to the epidermal growth factor receptor and attenuation of receptor signalling. J. Biol. Chem. 273, 24839–24846 (1998).

    CAS  PubMed  Google Scholar 

  98. 98

    Frank, C. et al. Effective dephosphorylation of Src substrates by SHP-1. J. Biol. Chem. 279, 11375–11383 (2004).

    CAS  PubMed  Google Scholar 

  99. 99

    Uchida, T. et al. Insulin stimulates the phosphorylation of Tyr538 and the catalytic activity of PTP1C, a protein tyrosine phosphatase with Src homology-2 domains. J. Biol. Chem. 269, 12220–8 (1994).

    CAS  PubMed  Google Scholar 

  100. 100

    Gierer, A. & Meinhardt, H. A theory of biological pattern formation. Kybernetik 12, 30–39 (1972).

    CAS  PubMed  Google Scholar 

  101. 101

    Goryachev, A. B. & Pokhilko, A. V. Dynamics of Cdc42 network embodies a Turing-type mechanism of yeast cell polarity. FEBS Lett. 582, 1437–1443 (2008).

    CAS  PubMed  Google Scholar 

  102. 102

    Meinhardt, H. Models for organizer and notochord formation. C R. Acad. Sci. III 323, 23–30 (2000).

    CAS  PubMed  Google Scholar 

  103. 103

    Wong, K., Pertz, O., Hahn, K. & Bourne, H. Neutrophil polarization: spatiotemporal dynamics of RhoA activity support a self-organizing mechanism. Proc. Natl Acad. Sci. USA 103, 3639–3644 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Xu, J. et al. Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils. Cell 114, 201–214 (2003).

    CAS  PubMed  Google Scholar 

  105. 105

    Narang, A. Spontaneous polarization in eukaryotic gradient sensing: a mathematical model based on mutual inhibition of frontness and backness pathways. J. Theor. Biol. 240, 538–553 (2006).

    CAS  PubMed  Google Scholar 

  106. 106

    Onsum, M. & Rao, C. V. A mathematical model for neutrophil gradient sensing and polarization. PLoS Comput. Biol. 3, 436–450 (2007).

    CAS  Google Scholar 

  107. 107

    Verkhovsky, A. B., Svitkina, T. M. & Borisy, G. G. Self-polarization and directional motility of cytoplasm. Curr. Biol. 9, 11–20 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Tabony, J. Microtubules viewed as molecular ant colonies. Biol. Cell 98, 603–617 (2006).

    CAS  PubMed  Google Scholar 

  109. 109

    Dumont, S. & Mitchison, T. J. Force and length in the mitotic spindle. Curr. Biol. 19, R749–R761 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Howard, J. Mechanical signalling in networks of motor and cytoskeletal proteins. Annu. Rev. Biophys. 38, 217–234 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Nedelec, F. J., Surrey, T., Maggs, A. C. & Leibler, S. Self-organization of microtubules and motors. Nature 389, 305–308 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Surrey, T., Nedelec, F., Leibler, S. & Karsenti, E. Physical properties determining self-organization of motors and microtubules. Science 292, 1167–1171 (2001). Spontaneous aster formation from artificially cross-linked molecular motors and dynamically growing microtubules is reconstituted in vitro using purified components and resulting structures are compared with computational simulations.

    CAS  PubMed  Google Scholar 

  113. 113

    Dehmelt, L., Nalbant, P., Steffen, W. & Halpain, S. A microtubule-based, dynein-dependent force induces local cell protrusions: implications for neurite initiation. Brain Cell Biol. 35, 39–56 (2006).

    CAS  PubMed  Google Scholar 

  114. 114

    Tischer, C. & Bastiaens, P. I. Lateral phosphorylation propagation: an aspect of feedback signalling? Nature Rev. Mol. Cell Biol. 4, 971–974 (2003).

    CAS  Google Scholar 

  115. 115

    Arrio-Dupont, M., Foucault, G., Vacher, M., Devaux, P. F. & Cribier, S. Translational diffusion of globular proteins in the cytoplasm of cultured muscle cells. Biophys. J. 78, 901–907 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Caviston, J. P. & Holzbaur, E. L. Microtubule motors at the intersection of trafficking and transport. Trends Cell Biol. 16, 530–537 (2006).

    CAS  PubMed  Google Scholar 

  117. 117

    Charras, G. T., Mitchison, T. J. & Mahadevan, L. Animal cell hydraulics. J. Cell Sci. 122, 3233–3241 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Hodgkin, A. L. & Huxley, A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117, 500–544 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Dawson, S. P., Keizer, J. & Pearson, J. E. Fire-diffuse-fire model of dynamics of intracellular calcium waves. Proc. Natl Acad. Sci. USA 96, 6060–6063 (1999).

    CAS  PubMed  Google Scholar 

  120. 120

    Sawano, A., Takayama, S., Matsuda, M. & Miyawaki, A. Lateral propagation of EGF signalling after local stimulation is dependent on receptor density. Dev. Cell 3, 245–257 (2002).

    CAS  Google Scholar 

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Acknowledgements

We thank the following colleagues from our department: A. Kraemer for help in preparing the manuscript, A. Chandra for providing the microscopic images in Figure 2a and M. Schmick for providing the cellular automaton simulation.

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Glossary

Dissipative system

A dynamic system that operates far out of equilibrium and exchanges energy and matter with its environment.

Stigmergy

Derived from the Greek 'stigma', meaning mark or sign, and 'ergon', meaning work or action. This concept was used to describe termite mound construction, in which the work in progress provides marks for further work.

Cytoplasmic state

One of a limited number of dynamically maintained, inter-converting states of an intracellular signalling network that define distinct cellular behaviours.

Fluorescence photobleaching

Irreversible photo-destruction of fluorescent molecules by prolonged and/or intense illumination.

Quantum dots

Inorganic, semi-conductor crystals, which are used as alternatives to organic fluorophore dyes owing to their bright fluorescence and high photostability

Diffraction pattern

A pattern, forming by constructive and destructive interference, that occurs if waves encounter an obstacle or a medium with varying refractive index. The interference pattern sets a limit to resolve two closely spaced structures by optical methods.

Total internal reflection fluorescence microscopy

A microscopy method in which total reflection is used to generate an exponentially decaying evanescent wave at a glass–water interface, with a depth of 50–300 nm, to selectively excite fluorescent molecules near a surface.

Multifocal plane microscopy

An extension to standard microscopy techniques in which multiple images at distinct focal planes are recorded simultaneously to allow the accurate positioning of particles in 3D.

Fluorescence correlation spectroscopy

A microscopic method to measure diffusion coefficients and concentrations of fluorescent molecules by detecting their passage through a small volume generated by the focus of a confocal microscope.

Fluorescence speckle microscopy

A microscopy method to determine protein mobilities by substochiometric fluorescent labelling of intracellular supramolecular structures.

Chromophore

The part of a molecule that absorbs visible light and thereby provides colour to the molecule. If the molecule re-emits excited-state energy as light, it is also a fluorophore.

Acceptor-sensitized emission

Fluorescence emission of an acceptor fluorophore that is excited by FRET.

Fluorescence lifetime imaging microscopy

A microscopy method to image the excited state lifetimes of fluorophores.

Solvatochromic dye

A fluorophore that changes its spectral properties owing to a change in solvent polarity.

Michaelis constant

The substrate concentration at which the rate of an enzymatic reaction (that is governed by Michaelis–Menten kinetics) is at half of its maximal value.

Michaelis–Menten kinetics

A widespread model for saturable enzyme kinetics, described in Michaelis, L., Menten, M. L. Biochem. Z. 49, 333–369 (1913).

Hysteresis

A path-dependent lag in a dynamic process, which leads to an asymmetry in forward and backward transitions.

Shmoo

A tip structure (named after a cartoon character) involved in cell fusion of mating yeast that emerges after pheromone stimulation.

Hydrodynamic radius

The radius of a hypothetical solid sphere that has the theoretical diffusional mobility of a measured particle in a given solvent.

Aster

The star-shaped geometric arrangement of filaments.

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Dehmelt, L., Bastiaens, P. Spatial organization of intracellular communication: insights from imaging. Nat Rev Mol Cell Biol 11, 440–452 (2010). https://doi.org/10.1038/nrm2903

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