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Bioinformatics Forum: Cell-Signaling Dynamics in Time and Space
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Boris N. Kholodenko (Systems Biology Institute, University College Dublin, Ireland)
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Thursday, 19.3.2009, 14:30
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Taub 601
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 spatio-temporal 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 spatio-temporal dynamics of signaling networks. Quantitative analysis of signal transduction is confronted by the combinatorial explosion of the number of feasible molecular species presenting different states of protein complexes that include receptors and scaffolds with multiple binding domains. We show that a mechanistic description of a highly combinatorial network may be drastically reduced using a “domain-oriented”, macro-modeling framework. Using this approach, we explored the role of the scaffold protein GAB1 in the control of mitogenic (Ras/MAPK) and survival (PI3K/Akt) signaling. Our findings demonstrate that the essential function of GAB1 is to enhance PI3K/Akt activation and extend the duration of Ras/MAPK signaling.

Recent discoveries changed our perception of the signal specificity, suggesting that this specificity is encoded by the spatial and temporal dynamics of downstream signaling networks. The ErbB receptors are the gatekeepers of a multilayered signal transduction network that converts external stimuli into specific gene expression responses and cell fate decisions. By combining computational modeling with experiments, we show how two ErbB receptor ligands, epidermal growth factor (EGF) and heregulin (HRG), induce distinct all-or-nothing 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 owing to induced expression of nuclear dual-specificity phosphatases (DUSP). Our results demonstrate that the distinct c-Fos responses arise from ligand-dependent, spatiotemporal control of ERK activity emerging from DUSP-mediated negative feedback and cytoplasmic-signaling-to-protein-expression feedforward loops. Cells have developed mechanisms for precise sensing of the positional information. We show that the spatial separation of opposing reactions in covalent-modification cycles results in the intracellular gradients of protein activities. These gradients provide positional cues for pivotal cellular processes, such as mitosis, motility and migration. The membrane confinement of initiating kinase (e.g., Ras/Raf in the MAPK cascade) and cytosolic localization of phosphatases can result in precipitous spatial gradients of phosphorylated kinases down the cascade, with high concentration near the membrane and low in the perinuclear area. This suggests a need for additional mechanisms that facilitate signaling to distant targets, including vesicular and non-vesicular trafficking of phosphorylated kinases driven by molecular motors. Rapid survival signals in neurons can be transmitted by waves of protein phosphorylation emerging in kinase/phosphatase cascades, such as MAPK, PI3K/Akt and GTPase cascades.

In addition to mechanistic modeling, a top-down approach to inferring the structure of cellular signaling and gene networks will be presented. We demonstrate how dynamic connections leading to a particular network node can be retrieved from experimentally measured network responses to perturbations influencing other nodes.

Host: Ron Pinter
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