Now showing 1 - 6 of 6
  • Publication
    Signalling over a distance: gradient patterns and phosphorylation waves within single cells
    (Portland Press, 2010-10-01) ;
    Recent discoveries of phosphorylation gradients and microdomains with different protein activities have revolutionized our perception of information transfer within single cells. The different spatial localization of opposing reactions in protein-modification cycles has been shown to bring about heterogeneous stationary patterns and travelling waves of protein activities. We review spatial patterns and modes of signal transfer through phosphorylation/dephosphorylation and GDP/GTP exchange cycles and cascades. We show how switches between low-activity and high-activity states in a bistable activation–deactivation cycle can initiate the propagation of travelling protein-modification waves in the cytoplasm. Typically, an activation wave is initiated at the plasma membrane and propagates through the cytoplasm until it reaches the nucleus. An increase in deactivator activity is followed by the initiation of an inactivation wave that moves in the reverse direction from the nucleus. We show that the ratio of opposing enzyme rates is a key parameter that controls both the spread of activation through cascades and travelling waves.
      320Scopus© Citations 21
  • Publication
    Switches, Excitable Responses and Oscillations in the Ring1B/Bmi1 Ubiquitination System
    (Public Library of Science, 2011-12-15) ; ; ;
    In an active, self-ubiquitinated state, the Ring1B ligase monoubiquitinates histone H2A playing a critical role in Polycomb-mediated gene silencing. Following ubiquitination by external ligases, Ring1B is targeted for proteosomal degradation. Using biochemical data and computational modeling, we show that the Ring1B ligase can exhibit abrupt switches, overshoot transitions and self-perpetuating oscillations between its distinct ubiquitination and activity states. These different Ring1B states display canonical or multiply branched, atypical polyubiquitin chains and involve association with the Polycomb-group protein Bmi1. Bistable switches and oscillations may lead to all-or-none histone H2A monoubiquitination rates and result in discrete periods of gene (in)activity. Switches, overshoots and oscillations in Ring1B catalytic activity and proteosomal degradation are controlled by the abundances of Bmi1 and Ring1B, and the activities and abundances of external ligases and deubiquitinases, such as E6-AP and USP7.
      226Scopus© Citations 28
  • Publication
    Formation of Intracellular Concentration Landscapes by Multisite Protein Modification
    Multiple cellular proteins are covalently modified (e.g., phosphorylated/dephosphorylated) at several sites, which leads to diverse signaling activities. Here, we consider a signaling cascade that is activated at the plasma membrane and composed of two-site protein modification cycles, and we focus on the radial profile of the concentration landscapes created by different protein forms in the cytoplasm. We show that under proper conditions, the concentrations of modified proteins generate a series of peaks that propagate into the cell interior. Proteins modified at both sites form activity gradients with long plateaus that abruptly decay at successive locations along the path from the membrane to the nucleus. We demonstrate under what conditions signals generated at the membrane stall in the vicinity of that membrane or propagate into the cell. We derive analytical approximations for the main characteristics of the protein concentration profiles and demonstrate what we believe to be a novel steady-state pattern formation mechanism capable of generating precise spatial guidance for diverse cellular processes.
      199Scopus© Citations 2
  • Publication
    Positional Information Generated by Spatially Distributed Signaling Cascades
    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.
      218Scopus© Citations 34
  • Publication
    Aggregation of chemotactic organisms in a differential flow
    (American Physical Society, 2009-12) ;
    We study the effect of advection on the aggregation and pattern formation in chemotactic systems described by Keller-Segel-type models. The evolution of small perturbations is studied analytically in the linear regime complemented by numerical simulations. We show that a uniform differential flow can significantly alter the spatial structure and dynamics of the chemotactic system. The flow leads to the formation of anisotropic aggregates that move following the direction of the flow, even when the chemotactic organisms are not directly advected by the flow. Sufficiently strong advection can stop the aggregation and coarsening process that is then restricted to the direction perpendicular to the flow.
      252Scopus© Citations 2
  • Publication
    Nutrient exposure of chemotactic organisms in small-scale turbulent flows
    Micro-organisms living in a turbulent fluid environment often use directed motility to locate regions of higher than average nutrient concentrations. Here, we consider a simple continuum model for the distribution of such chemotactic particles when the particles and the chemoattractant are both advected by a turbulent flow. The influence of chemotactic sensitivity on the spatial distribution of the particles is characterized for different types of advected chemical fields. Using an effective diffusion approximation, we obtain an analytical expression for the nutrient exposure resulting from the chemotactic activity of the particles, generalizing previous results obtained for the case of phototaxis in flows. We show that the biological advantage of chemotaxis in such systems is determined by the spatial variability of the averaged chemoattractant field and the effective diffusivity of the turbulent flow.
      212Scopus© Citations 6