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  • Review Article
  • Published:

Signalling ballet in space and time

Nature Reviews Molecular Cell Biology volume 11, pages 414–426 (2010)Cite this article

Subjects

Key Points

  • Spatiotemporal network dynamics govern cell fate decisions. We use the extracellular signal-regulated kinase (ERK) pathway as a paradigm to describe how temporal activation kinetics and spatial organization control biological decisions.

  • Signalling circuits can operate as analogue-to-digital converters, generating abrupt switches, multistable dynamics, excitable pulses and oscillations. These distinct outputs facilitate signal discrimination by target gene networks and control cell phenotypic responses.

  • The transfer of information through signalling networks is regulated at several levels and includes spatiotemporal control. Multiple regulatory motifs, such as feedback and feed-forward phosphorylation loops, and crosstalk between pathways provide robustness and fidelity of the input–output responses.

  • Scaffolding proteins physically link pathway components, thereby forming signalling modules that markedly affect spatiotemporal control of signalling and specificity of inputs and outputs. Scaffolds often also localize these signalling units to distinct subcellular compartments and can allosterically regulate binding partners.

  • Nanoscale and microscale signalling domains are highly dynamic structures that form in membrane compartments. Well-characterized domains are Ras nanoclusters that may have a crucial control in input–output relationships in the Ras–Raf–MAPK/ERK kinase–ERK pathway.

  • Distinct spatial domains can also arise from chemical reactions coupled with diffusion. Combined with the distinct localization of enzymes, these processes generate intricate concentration landscapes of enzymatic reactivities, macromolecules and second messengers within cells.

Abstract

Although we have amassed extensive catalogues of signalling network components, our understanding of the spatiotemporal control of emergent network structures has lagged behind. Dynamic behaviour is starting to be explored throughout the genome, but analysis of spatial behaviours is still confined to individual proteins. The challenge is to reveal how cells integrate temporal and spatial information to determine specific biological functions. Key findings are the discovery of molecular signalling machines such as Ras nanoclusters, spatial activity gradients and flexible network circuitries that involve transcriptional feedback. They reveal design principles of spatiotemporal organization that are crucial for network function and cell fate decisions.

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Figure 1: Versatile MAPK dynamics.
Figure 2: Intrinsic transcriptional feedback inhibition of NF-κB.
Figure 3: Scaffolds and spatial organization.
Figure 4: Ras nanoclusters digitize transmembrane signal transmission.

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References

  1. Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995). A conceptual breakthrough summarizing many experimental observations that different durations of ERK activity can result in different phenotypic responses.

    Article  CAS  PubMed  Google Scholar 

  2. Murphy, L. O., MacKeigan, J. P. & Blenis, J. A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration. Mol. Cell. Biol. 24, 144–153 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. von Kriegsheim, A. et al. Cell fate decisions are specified by the dynamic ERK interactome. Nature Cell Biol. 11, 1458–1464 (2009). Provides insight into a full set of protein–protein interactions involving ERK, and shows how ERK partners control ERK spatiotemporal dynamics and cell decisions.

    Article  CAS  PubMed  Google Scholar 

  4. Nakakuki, T. et al. Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics. Cell 20 May 2010 (doi:10.16/j.cell.2010.03.054)

  5. Meloche, S. & Pouyssegur, J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 26, 3227–3239 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Nagashima, T. et al. Quantitative transcriptional control of ErbB receptor signaling undergoes graded to biphasic response for cell differentiation. J. Biol. Chem. 282, 4045–4056 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. McCawley, L. J., Li, S., Wattenberg, E. V. & Hudson, L. G. Sustained activation of the mitogen-activated protein kinase pathway. A mechanism underlying receptor tyrosine kinase specificity for matrix metalloproteinase-9 induction and cell migration. J. Biol. Chem. 274, 4347–4353 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Kholodenko, B. N. Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. Eur. J. Biochem. 267, 1583–1588 (2000). Predicted sustained MAPK oscillations that were later discovered experimentally (see references 12 and 14).

    Article  CAS  PubMed  Google Scholar 

  9. Brightman, F. A. & Fell, D. A. Differential feedback regulation of the MAPK cascade underlies the quantitative differences in EGF and NGF signalling in PC12 cells. FEBS Lett. 482, 169–174 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Kiyatkin, A. et al. Scaffolding protein Grb2-associated binder 1 sustains epidermal growth factor-induced mitogenic and survival signaling by multiple positive feedback loops. J. Biol. Chem. 281, 19925–19938 (2006). A working model of combinatorially complex interactions of multidomain proteins that control phosphoinositide 3-kinase and ERK pathway crosstalk.

    Article  CAS  PubMed  Google Scholar 

  11. Birtwistle, M. R. et al. Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses. Mol. Syst. Biol. 3, 144 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nakayama, K., Satoh, T., Igari, A., Kageyama, R. & Nishida, E. FGF induces oscillations of Hes1 expression and Ras/ERK activation. Curr. Biol. 18, R332–R334 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Das, J. et al. Digital signaling and hysteresis characterize Ras activation in lymphoid cells. Cell 136, 337–351 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shankaran, H. et al. Rapid and sustained nuclear-cytoplasmic ERK oscillations induced by epidermal growth factor. Mol. Syst. Biol. 5, 332 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dougherty, M. K. et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol. Cell 17, 215–224 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Shin, S. Y. et al. Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway. J. Cell Sci. 122, 425–435 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Douville, E. & Downward, J. EGF induced SOS phosphorylation in PC12 cells involves P90 RSK-2. Oncogene 15, 373–383 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Markevich, N. I., Hoek, J. B. & Kholodenko, B. N. Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. J. Cell Biol. 164, 353–359 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Qiao, L., Nachbar, R. B., Kevrekidis, I. G. & Shvartsman, S. Y. Bistability and oscillations in the Huang-Ferrell model of MAPK signaling. PLoS Comput. Biol. 3, 1819–1826 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Kholodenko, B. N. Untangling the signalling wires. Nature Cell Biol. 9, 247–249 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Kholodenko, B. N. et al. Untangling the wires: a strategy to trace functional interactions in signaling and gene networks. Proc. Natl Acad. Sci. USA 99, 12841–12846 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Santos, S. D., Verveer, P. J. & Bastiaens, P. I. Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nature Cell Biol. 9, 324–330 (2007). Direct experimental determination of context-dependent and time-varying topology of dynamic connections between MAPK cascade components.

    Article  CAS  PubMed  Google Scholar 

  23. Brondello, J. M., Brunet, A., Pouyssegur, J. & McKenzie, F. R. The dual specificity mitogen-activated protein kinase phosphatase-1 and -2 are induced by the p42/p44MAPK cascade. J. Biol. Chem. 272, 1368–1376 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Patterson, K. I., Brummer, T., O'Brien, P. M. & Daly, R. J. Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem. J. 418, 475–489 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Amit, I. et al. A module of negative feedback regulators defines growth factor signaling. Nature Genet. 39, 503–512 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Legewie, S., Herzel, H., Westerhoff, H. V. & Bluthgen, N. Recurrent design patterns in the feedback regulation of the mammalian signalling network. Mol. Syst. Biol. 4, 190 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Hilioti, Z. et al. Oscillatory phosphorylation of yeast Fus3 MAP kinase controls periodic gene expression and morphogenesis. Curr. Biol. 18, 1700–1706 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sigal, A. et al. Variability and memory of protein levels in human cells. Nature 444, 643–646 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Tyson, J. J., Chen, K. C. & Novak, B. Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr. Opin. Cell Biol. 15, 221–231 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Wang, X., Hao, N., Dohlman, H. G. & Elston, T. C. Bistability, stochasticity, and oscillations in the mitogen-activated protein kinase cascade. Biophys. J. 90, 1961–1978 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Kaimachnikov, N. P. & Kholodenko, B. N. Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle. FEBS J. 276, 4102–4118 (2009).

    CAS  Google Scholar 

  33. 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).

    Article  CAS  PubMed  Google Scholar 

  34. Bagowski, C. P. & Ferrell, J. E. Jr. Bistability in the JNK cascade. Curr. Biol. 11, 1176–1182 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Freedman, T. S. et al. A Ras-induced conformational switch in the Ras activator Son of sevenless. Proc. Natl Acad. Sci. USA 103, 16692–16697 (2006). Direct experimental evidence of Ras–SOS positive feedback.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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). Demonstrates how a short and prolonged duration of ERK signalling can be sensed at the level of IEGs.

    Article  CAS  PubMed  Google Scholar 

  37. Mangan, S., Zaslaver, A. & Alon, U. The coherent feedforward loop serves as a sign-sensitive delay element in transcription networks. J. Mol. Biol. 334, 197–204 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Vomastek, T. et al. Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists. Proc. Natl Acad. Sci. USA 101, 6981–6986 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Teis, D., Wunderlich, W. & Huber, L. A. Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction. Dev. Cell 3, 803–814 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Vallabhapurapu, S. & Karin, M. Regulation and function of NF-κB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693–733 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Wertz, I.E. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF- κB signalling. Nature 430, 694–699 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Ashall, L. et al. Pulsatile stimulation determines timing and specificity of NF-κB-dependent transcription. Science 324, 242–246 (2009). Provides a combined experimental and mathematical analysis of the nucleo-cytoplasmic shuttling cycles of NF-κB and how they relate to specifying gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, D., Kolch, W. & Cho, K. H. Multiple roles of the NF-κB signaling pathway regulated by coupled negative feedback circuits. FASEB J. 23, 2796–2802 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Beene, D. L. & Scott, J. D. A-kinase anchoring proteins take shape. Curr. Opin. Cell Biol. 19, 192–198 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kolch, W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nature Rev. Mol. Cell Biol. 6, 827–837 (2005).

    Article  CAS  Google Scholar 

  46. McKay, M. M. & Morrison, D. K. Integrating signals from RTKs to ERK/MAPK. Oncogene 26, 3113–3121 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Shaw, A. S. & Filbert, E. L. Scaffold proteins and immune-cell signalling. Nature Rev. Immunol. 9, 47–56 (2009).

    Article  CAS  Google Scholar 

  48. DeWire, S. M., Ahn, S., Lefkowitz, R. J. & Shenoy, S. K. β-arrestins and cell signaling. Annu. Rev. Physiol. 69, 483–510 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Perry, S. J. et al. Targeting of cyclic AMP degradation to β2-adrenergic receptors by β-arrestins. Science 298, 834–836 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Nelson, C. D. et al. Targeting of diacylglycerol degradation to M1 muscarinic receptors by β-arrestins. Science 315, 663–666 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Tanoue, T. & Nishida, E. Molecular recognitions in the MAP kinase cascades. Cell Signal. 15, 455–462 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Levchenko, A., Bruck, J. & Sternberg, P. W. Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties. Proc. Natl Acad. Sci. USA 97, 5818–5823 (2000). A kinetic model showing that scaffold organization of a kinase cascade markedly changes the input–output relationships.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Casar, B. et al. Ras subcellular localization defines extracellular signal-regulated kinase 1 and 2 substrate specificity through distinct utilization of scaffold proteins. Mol. Cell Biol. 29, 1338–1353 (2009). Provides insight in how Ras signalling from different membrane compartments uses different scaffold proteins for the ERK pathway to selectively target downstream ERK substrates.

    Article  CAS  PubMed  Google Scholar 

  54. Chiu, V. K. et al. Ras signalling on the endoplasmic reticulum and the Golgi. Nature Cell Biol. 4, 343–350 (2002). Shows that Ras signalling can emanate from different subcellular membrane compartments and activate different downstream pathways.

    Article  CAS  PubMed  Google Scholar 

  55. Rajakulendran, T., Sahmi, M., Lefrancois, M., Sicheri, F. & Therrien, M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature 461, 542–545 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Bhattacharyya, R. P. et al. The Ste5 scaffold allosterically modulates signaling output of the yeast mating pathway. Science 311, 822–826 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Good, M., Tang, G., Singleton, J., Remenyi, A. & Lim, W. A. The Ste5 scaffold directs mating signaling by catalytically unlocking the Fus3 MAP kinase for activation. Cell 136, 1085–1097 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Takahashi, S. & Pryciak, P. M. Membrane localization of scaffold proteins promotes graded signaling in the yeast MAP kinase cascade. Curr. Biol. 18, 1184–1191 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rizzuto, R. et al. Ca2+ transfer from the ER to mitochondria: when, how and why. Biochim. Biophys. Acta 1787, 1342–1351 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kornmann, B. et al. An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science 325, 477–481 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Roos, J. et al. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J. Cell Biol. 169, 435–445 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Park, C. Y. et al. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136, 876–890 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kusumi, A. et al. Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: high-speed single-molecule tracking of membrane molecules. Annu. Rev. Biophys. Biomol. Struct. 34, 351–378 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Simons, K. & Toomre, D. Lipid rafts and signal transduction. Nature Rev. Mol. Cell Biol. 1, 31–39 (2000).

    Article  CAS  Google Scholar 

  65. Eggeling, C. et al. Direct observation of the nanoscale dynamics of membrane lipids in a living cell. Nature 457, 1159–1162 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Sharma, P. et al. Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell 116, 577–589 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Hancock, J. F. Lipid rafts: contentious only from simplistic standpoints. Nature Rev. Mol. Cell Biol. 7, 456–462 (2006).

    Article  CAS  Google Scholar 

  68. Hanzal-Bayer, M. F. & Hancock, J. F. Lipid rafts and membrane traffic. FEBS Lett. 581, 2098–2104 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Nicolau, D. V. Jr, Burrage, K., Parton, R. G. & Hancock, J. F. Identifying optimal lipid raft characteristics required to promote nanoscale protein-protein interactions on the plasma membrane. Mol. Cell Biol. 26, 313–323 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hancock, J. F., Paterson, H. & Marshall, C. J. A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane. Cell 63, 133–139 (1990).

    Article  CAS  PubMed  Google Scholar 

  71. Hancock, J. F. & Parton, R. G. Ras plasma membrane signalling platforms. Biochem. J. 389, 1–11 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Plowman, S. J., Muncke, C., Parton, R. G. & Hancock, J. F. H-ras, K-ras, and inner plasma membrane raft proteins operate in nanoclusters with differential dependence on the actin cytoskeleton. Proc. Natl Acad. Sci. USA 102, 15500–15505 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Murakoshi, H. et al. Single-molecule imaging analysis of Ras activation in living cells. Proc. Natl Acad. Sci. USA 101, 7317–7322 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Belanis, L., Plowman, S. J., Rotblat, B., Hancock, J. F. & Kloog, Y. Galectin-1 is a novel structural component and a major regulator of h-ras nanoclusters. Mol. Biol. Cell 19, 1404–1414 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Shalom-Feuerstein, R. et al. K-ras nanoclustering is subverted by overexpression of the scaffold protein galectin-3. Cancer Res. 68, 6608–6616 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Plowman, S. J., Ariotti, N., Goodall, A., Parton, R. G. & Hancock, J. F. Electrostatic interactions positively regulate K-Ras nanocluster formation and function. Mol. Cell. Biol. 28, 4377–4385 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Abankwa, D., Gorfe, A. G., Inder, K. & Hancock, J. F. Ras membrane orientation and nanodomain localization generate isoform diversity. Proc. Natl Acad. Sci. USA 107, 1130–1135 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Tian, T. et al. Plasma membrane nanoswitches generate high-fidelity Ras signal transduction. Nature Cell Biol. 9, 905–914 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Harding, A., Tian, T., Westbury, E., Frische, E. & Hancock, J. F. Subcellular localization determines MAP kinase signal output. Curr. Biol. 15, 869–873 (2005). Shows that in mammalian cells the MAPK cascade can operate as a switch with different sensitivity to the input signals from the plasma membrane and cytoplasm.

    Article  CAS  PubMed  Google Scholar 

  80. Inder, K. et al. Activation of the MAPK module from different spatial locations generates distinct system outputs. Mol. Biol. Cell 19, 4776–4784 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Harding, A. S. & Hancock, J. F. Using plasma membrane nanoclusters to build better signaling circuits. Trends Cell Biol. 18, 364–371 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Suzuki, K. G., Fujiwara, T. K., Edidin, M. & Kusumi, A. Dynamic recruitment of phospholipase Cγ at transiently immobilized GPI-anchored receptor clusters induces IP3-Ca2+ signaling: single-molecule tracking study 2. J. Cell Biol. 177, 731–742 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Suzuki, K. G. et al. GPI-anchored receptor clusters transiently recruit Lyn and Gα for temporary cluster immobilization and Lyn activation: single-molecule tracking study 1. J. Cell Biol. 177, 717–730 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Goswami, D. et al. Nanoclusters of GPI-anchored proteins are formed by cortical actin-driven activity. Cell 135, 1085–1097 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Daniels, M. A. et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444, 724–729 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Turing, A. M. The chemical basis of morphogenesis. Phil. Trans. R. Soc. Lond. B Biol. Sci. 237, 37–72 (1952). Shows that diffusion can destabilize spatially uniform steady-state distribution, resulting in heterogeneous spatial concentration patterns.

    Article  Google Scholar 

  87. Gierer, A. Generation of biological patterns and form: some physical, mathematical, and logical aspects. Prog. Biophys. Mol. Biol. 37, 1–47 (1981).

    Article  CAS  PubMed  Google Scholar 

  88. Brown, G. C. & Kholodenko, B. N. Spatial gradients of cellular phospho-proteins. FEBS Lett. 457, 452–454 (1999). Shows that the spatial separation of opposing enzymes in a protein modification cycle brings about protein activity gradients and non-uniform spatial profiles.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    Article  CAS  PubMed  Google Scholar 

  91. Yudushkin, I. A. et al. Live-cell imaging of enzyme-substrate interaction reveals spatial regulation of PTP1B. Science 315, 115–119 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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).

    Article  CAS  PubMed  Google Scholar 

  94. Kholodenko, B. N. Spatially distributed cell signalling. FEBS Lett. 583, 4006–4012 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Stelling, J. & Kholodenko, B. N. Signaling cascades as cellular devices for spatial computations. J. Math. Biol. 58, 35–55 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Kholodenko, B. N. MAP kinase cascade signaling and endocytic trafficking: a marriage of convenience? Trends Cell Biol. 12, 173–177 (2002). Shows theoretically that the propagation of phosphorylation signals solely by diffusion can be terminated by cytoplasmic phosphatases. The study suggests that in large cells, motor-driven trafficking of endosomes and scaffolds carrying phosphorylated kinases or assembled signalling complexes is required for signal transduction.

    Article  CAS  PubMed  Google Scholar 

  97. Munoz-Garcia, J., Neufeld, Z. & Kholodenko, B. N. Positional information generated by spatially distributed signaling cascades. PLoS Comput. Biol. 5, e1000330 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Takai, Y., Sasaki, T. & Matozaki, T. Small GTP-binding proteins. Physiol. Rev. 81, 153–208 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Athale, C. A. et al. Regulation of microtubule dynamics by reaction cascades around chromosomes. Science 322, 1243–1247 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Markevich, N. I., Tsyganov, M. A., Hoek, J. B. & Kholodenko, B. N. Long-range signaling by phosphoprotein waves arising from bistability in protein kinase cascades. Mol. Syst. Biol. 2, 61 (2006). Shows the possibility of waves of protein phosphorylation travelling through the cytoplasm or long neuron axons.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Levine, H. & Rappel, W. J. Membrane-bound Turing patterns. Phys. Rev. E Stat. Nonlin Soft Matter Phys. 72, 061912 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. 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).

    Article  CAS  PubMed  Google Scholar 

  103. Mori, Y., Jilkine, A. & Edelstein-Keshet, L. Wave-pinning and cell polarity from a bistable reaction-diffusion system. Biophys. J. 94, 3684–3697 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Meyers, J., Craig, J. & Odde, D. J. Potential for control of signaling pathways via cell size and shape. Curr. Biol. 16, 1685–1693 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Neves, S. R. et al. Cell shape and negative links in regulatory motifs together control spatial information flow in signaling networks. Cell 133, 666–680 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Borisov, N. et al. Systems-level interactions between insulin-EGF networks amplify mitogenic signaling. Mol. Syst. Biol. 5, 256 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wang, C. C., Cirit, M. & Haugh, J. M. PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk. Mol. Syst. Biol. 5, 246 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Berezhkovskii, A. M., Coppey, M. & Shvartsman, S. Y. Signaling gradients in cascades of two-state reaction-diffusion systems. Proc. Natl Acad. Sci. USA 106, 1087–1092 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kholodenko, B. N. & Kolch, W. Giving space to cell signaling. Cell 133, 566–567 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Neves, S. R. & Iyengar, R. Models of spatially restricted biochemical reaction systems. J. Biol. Chem. 284, 5445–5449 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kholodenko, B. N. Four-dimensional organization of protein kinase signaling cascades: the roles of diffusion, endocytosis and molecular motors. J. Exp. Biol. 206, 2073–2082 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Rishal, I. & Fainzilber, M. Retrograde signaling in axonal regeneration. Exp. Neurol. 223, 5–10 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Luttrell, L. M. Composition and function of G protein-coupled receptor signalsomes controlling mitogen-activated protein kinase activity. J. Mol. Neurosci. 26, 253–264 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Fehrenbacher, N., Bar-Sagi, D. & Philips, M. Ras/MAPK signaling from endomembranes. Mol. Oncol. 3, 297–307 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank M. Tsyganov, J. Muñoz García, A. Kiyatkin and N. Kaimachnikov for discussions. This work was supported by Science Foundation Ireland under Grant No. 06/CE/B1129 and National Institutes of Health grants GM059570, GM066717. We apologize about not citing many pertinent contributions to the field because of space limitations.

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Authors and Affiliations

  1. Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland

    Boris N. Kholodenko & Walter Kolch

  2. Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, USA

    Boris N. Kholodenko

  3. Department of Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, 77030, Texas, USA

    John F. Hancock

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  1. Boris N. Kholodenko
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Correspondence to Boris N. Kholodenko.

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Nature pathway interaction database for Ras

Nature pathway interaction database for MEK

Nature pathway interaction database for ERK

Glossary

Temporal dynamics

A quantitative description of how the system's behaviour changes over time.

Pheochromocytoma

An adrenal gland tumour that originates from cells derived from the neural crest.

Adenocarcinoma

A cancer arising in glandular parts of epithelial tissues.

Non-processive

Reaction mechanism in which the reactants dissociate after each partial reaction and have to encounter again for a new reaction. For instance, MEK phosphorylates ERK on two sites in a non-processive reaction that requires two distinct MEK–ERK interactions, in which only one site is phosphorylated per interaction event.

Spatiotemporal dynamics

A description of how the system behaviour changes in space and time.

Perfect adaptation

A term that, in control engineering, indicates the control strategy ensuring that the system output follows the desired course regardless of noise and variations in system parameters.

Damped oscillations

Oscillations the amplitude of which decreases to zero while the system approaches a steady state.

Sustained oscillations

Oscillations that continue indefinitely in time with constant amplitude and frequency.

Guanine nucleotide exchange factor

A protein that catalyses the exchange of GDP for GTP for a GTP-binding protein.

Ordinary differential equation

An equation in which differentiation occurs with respect to only a single independent variable, which is time for chemical kinetic equations.

Analogue signal

A signal the quantity of which (for example, the concentration or activity (amplitude)) changes continuously in time and space, gradually increasing or decreasing.

Digital output

A non-continuous signal that displays discrete levels, for instance zero or one.

Interactome

The complete set of protein–protein interactions in a cell or organism. Interactome is often also used to designate the set of interaction partners of individual proteins.

Partial differential equation

Contains partial derivatives with respect to two or more independent variables, which are time and the spatial coordinates for reaction–diffusion equations.

GTPase-activating protein

A protein that facilitates the hydrolysis of GTP by a GTP-binding protein.

Nanocluster

A transient, nanoscale array of plasma membrane proteins formed by lipid sorting and/or protein–protein interactions.

4-Pi

A laser scanning fluorescence microscope that uses two opposing objectives to improve axial spatial resolution.

Stimulated emission depletion

A fluorescence microscopy technique that uses nonlinear de-excitation of fluorescent dyes to improve the spatial resolution of standard confocal microscopy.

Farnesylation

A post-translational modification in which a farnesyl group (a hydrophobic group of three isoprene units) is conjugated to proteins, such as Ras GTPases, that contain a C-terminal CAAX motif. Farnesylation promotes attachment of the modified proteins to membranes.

Hysteresis

A system that relates current inputs to different steady-state outputs, depending on the previous state of the system; that is, hysteresis provides a memory function to a system.

Heterotrimeric G protein

A protein complex of three proteins (Gα, Gβ and Gγ). Gβ and Gγ form a tight complex, whereas Gα is part of the complex in its inactive, GDP-bound, form but dissociates in its active, GTP-bound, form. Both Gα and Gβγ can transmit downstream signals after activation.

Phosphorylation gradient

A gradual change in the fraction of phosphorylated protein with distance

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Kholodenko, B., Hancock, J. & Kolch, W. Signalling ballet in space and time. Nat Rev Mol Cell Biol 11, 414–426 (2010). https://doi.org/10.1038/nrm2901

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