Skip to main content
Article thumbnail
Location of Repository

Positional Information Generated by Spatially Distributed Signaling Cascades

By Javier Muñoz-García, Zoltan Neufeld and Boris N. Kholodenko


The temporal and stationary behavior of protein modification cascades has been extensively studied, yet little is known about the spatial aspects of signal propagation. We have previously shown that the spatial separation of opposing enzymes, such as a kinase and a phosphatase, creates signaling activity gradients. Here we show under what conditions signals stall in the space or robustly propagate through spatially distributed signaling cascades. Robust signal propagation results in activity gradients with long plateaus, which abruptly decay at successive spatial locations. We derive an approximate analytical solution that relates the maximal amplitude and propagation length of each activation profile with the cascade level, protein diffusivity, and the ratio of the opposing enzyme activities. The control of the spatial signal propagation appears to be very different from the control of transient temporal responses for spatially homogenous cascades. For spatially distributed cascades where activating and deactivating enzymes operate far from saturation, the ratio of the opposing enzyme activities is shown to be a key parameter controlling signal propagation. The signaling gradients characteristic for robust signal propagation exemplify a pattern formation mechanism that generates precise spatial guidance for multiple cellular processes and conveys information about the cell size to the nucleus

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (2001). A computational study of feedback effects on signal dynamics in a mitogen-activated protein kinase (mapk) pathway model.
  2. (2005). A molecular model for axon guidance based on cross talk between rho GTPases.
  3. (2003). A positive-feedback-based bistable ‘memory module’ that governs a cell fate decision.
  4. (1995). A viable reaction-diffusion wave on the skin of Pomacanthus, the marine Angelfish.
  5. (1981). An Amplified Sensitivity Arising from Covalent Modification in Biological Systems.
  6. (2007). Bistability and oscillations in the Huang-Ferrell model of MAPK signaling.
  7. (2008). Cell shape and negative links in regulatory motifs together control spatial information flow in signaling networks.
  8. (2006). Cell-signalling dynamics in time and space.
  9. (2003). Control of spatially heterogeneous and time-varying cellular reaction networks: a new summation law.
  10. (1992). Control of the metabolic flux in a system with high enzyme concentrations and moiety-conserved cycles. The sum of the flux control coefficients can drop significantly below unity.
  11. (2000). Differential feedback regulation of the MAPK cascade underlies the quantitative differences in EGF and NGF signalling
  12. (2006). Effects of sequestration on signal transduction cascades.
  13. (2007). Enzyme localization can drastically affect signal amplification in signal transduction pathways.
  14. (2008). FGF induces oscillations of Hes1 expression and Ras/ERK activation.
  15. (2003). Four-dimensional organization of protein kinase signaling cascades: the roles of diffusion, endocytosis and molecular motors.
  16. (2007). Fundamental limits to position determination by concentration gradients.
  17. (2004). General considerations for proteolytic cascades.
  18. (2008). Giving space to cell signaling.
  19. (1997). How responses get more switch-like as you move down a protein kinase cascade [letter; comment].
  20. (2006). Long-range signaling by phosphoprotein waves arising from bistability in protein kinase cascades.
  21. (2001). Mammalian MAP kinase signalling cascades.
  22. (2002). MAP kinase cascade signaling and endocytic trafficking: a marriage of convenience?
  23. (2007). Mathematical model for spatial segregation of the Rho-family GTPases based on inhibitory crosstalk.
  24. (2002). Mathematical models of protein kinase signal transduction.
  25. (2008). Midzone activation of aurora B in anaphase produces an intracellular phosphorylation gradient.
  26. (2000). Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades.
  27. (2006). Potential for Control of Signaling Pathways via Cell Size and Shape.
  28. (1997). Quantification of information transfer via cellular signal transduction pathways [published erratum appears in FEBS Lett
  29. (2006). Reading protein modifications with interaction domains.
  30. (2008). Signaling cascades as cellular devices for spatial computations.
  31. (2001). Small GTP-binding proteins.
  32. (1999). Spatial gradients of cellular phosphoproteins.
  33. (2007). Spatial regulation of Fus3 MAP kinase activity through a reaction-diffusion mechanism in yeast pheromone signalling.
  34. (2004). Stathmin-tubulin interaction gradients in motile and mitotic cells.
  35. (1977). Superiority of Interconvertible Enzyme Cascades in Metabolic Regulation: Analysis of Monocyclic Systems.
  36. (2007). Synthetic Turing protocells: vesicle self-reproduction through symmetry-breaking instabilities.
  37. (1952). The chemical basis of morphogenesis.
  38. (2006). The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions.
  39. (2006). Vimentin binding to phosphorylated Erk sterically hinders enzymatic dephosphorylation of the kinase.
  40. (2005). Vimentin-dependent spatial translocation of an activated MAP kinase in injured nerve.
  41. (2002). Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts.
  42. (2008). Wave-pinning and cell polarity from a bistable reaction-diffusion system.
  43. (2006). WNT and DKK Determine Hair Follicle Spacing Through a Reaction-Diffusion Mechanism.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.