The Second International Workshop on Static Analysis and Systems Biology (SASB 2011)

SAS workshop, 13 September 2011, Venice, Italie.


Invited talks

9h00-10h00: Invited Talk

  • Boris Kholodenko

    Systems Biology Ireland, University College Dublin, Betfield, Dublin, Ireland

    Signalling ballet in four dimensions.

    Extracellular information received by plasma membrane receptors is encoded into complex temporal and spatial patterns of phosphorylation and topological relocation of signaling proteins. Integration of this information by protein kinase cascades creates the spatiotemporal code that confers signaling specificity and leads to important decisions that determine cell's fate. Aberrant processing of signalling information is a leading cause of many human diseases that range from developmental defects to cancer, chronic inflammatory syndromes and diabetes. We employ computational and experimental approaches to reveal kinetic and molecular factors that control the spatiotemporal dynamics of signaling networks.

    Cells have developed mechanisms for precise sensing of positional information. We show how the spatial separation of opposing enzymes in covalent-modification cycles results in the intracellular gradients of protein activities. The membrane confinement of initiating kinase (e.g., Ras/Raf in the MAPK cascade) and cytosolic localization of phosphatases result in precipitous spatial gradients of phosphorylated kinases. A spatially distributed signalling cascade can create step-like activation profiles, which decay at successive distances from the cell surface, assigning digital positional information to different regions in the cell. Feedback and feedforward network motifs control activity patterns, allowing signalling networks to serve as cellular devices for spatial computations. Additional mechanisms that facilitate signal propagation to distant targets include vesicular and non-vesicular trafficking of phosphorylated kinases driven by molecular motors. Rapid survival signals in neurons might be transmitted by waves of protein phosphorylation emerging in kinase/phosphatase cascades, such as MAPK, PI3K/AKT and GTPase cascades.

    Cells respond to countless external cues using a limited repertoire of interconnected signalling pathways. Using modelling and experiments, we unravel how epidermal growth factor (EGF) and heregulin (HRG), induce distinct none-or-all responses of the transcription factor c-Fos by activating the extracellular regulated kinase (ERK) pathway. Although EGF and HRG induce transient versus sustained ERK activation in the cytoplasm, the nuclear ERK activity and the resulting c-fos mRNA expression are transient for both ligands due to induced nuclear dual-specificity phosphatases. Our data demonstrate that the distinct c-Fos responses arise from ligand-dependent, spatiotemporal control of ERK activity emerging from transcriptional negative feedback and cytoplasmic-signalling-to-protein-expression feedforward loops.


    1. Borisov et al (2009) Systems-level interactions between insulin-EGF networks amplify mitogenic signaling, Mol. Syst. Biol. 5, 256.
    2. Kholodenko, B. N., Hancock, J. F. & Kolch, W. (2010) Signalling ballet in space and time. Nat Rev Mol Cell Biol. 11, 414-426.
    3. Nakakuki et al (2010) Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics, Cell. 141, 884-896.
    4. Sturm et al (2010) The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier, Sci Signal. 3(153): ra90.

11h30-12h30: Invited Talk

  • Jean Krivine

    Université Paris VII & CNRS, France

    Formal Cellular Machinery.

    (joint work with Troels C. Damgaard and Espen Højsgaard, ITU Copenhagen)

    It has been about 10 years now that part of the theoretical computer science community got interested in applying formal methods to systems biology. Since then it seems that the quest for a calculus having proteins, compartments or channels as first class citizens has not reached an end. Among the large variety of languages that have been proposed to tackle various aspects of systems biology, several ideas seem of particular importance to us: (i) the cellular medium can be described as a graph where nodes represent molecules and edges represent physical contacts between these molecules, (ii) languages with a natural notion of location of reaction can be used to represent cellular compartments, (iii) interactions between compartments and proteins or vesicle transformations can be described using local patches of membranes, without committing to any particular global curvature and (iv) although laws governing interactions of molecular components are numerous, they can be engendered by a small set of generators.

    In this talk we will show how one may integrate points (i) to (iv) in a single formalism. More specifically we define a language for proteins and cells in an incremental way, making explicit the trade-off between expressiveness and complexity. The language we build is closely related to Milner's bigraphical reactive systems however this connection will be left informal throughout the talk.

17h00-18h00: Invited Talk

  • Edda Klipp.

    Humboldt-Universität zu Berlin, Theoretical Biophysics

    Zooming in on and out the eukaryotic cell cycle.

    Cells have to grow and to divide. This is a well-organized, highly regulated process. Since cells also have to react to changes in the environment, cell cycle must be both robust against and sensitive to changes. The ability to perceive and respond to information in their environment is one of the most ubiquitous properties of cellular organisms. It is crucial for a cell to react appropriately to changes or signals in its environment. This becomes apparent in many situations such as the search for nutrients, the detection of potentially harmful external conditions and in cell-cell communication as it is required for any multi- cellular organism. Even though there is a huge selection of perceivable signals the underlying mechanisms are surprisingly alike, which suggests that they are highly conserved in the course of evolution. Here, we apply different modeling techniques to understand cell cycle progression and cell cycle regulation in changing environments, with specific focus on mechanisms and experimental data for the model organism Saccharomyces cerevisiae. Specifically, new aspects in cell cycle regulation and the interaction of stress-activated signaling pathways with cell cycle progression will be discussed. The results indicate that yeast cells have developed different mechanisms for coping with external stress during different periods of their life time.