http://hdl.handle.net/10033/214051 Tue, 21 May 2013 11:25:25 GMT 2013-05-21T11:25:25Z http://hdl.handle.net/10033/267853 Title: Simulated evolution of signal transduction networks. Authors: Mobashir, Mohammad; Schraven, Burkhart; Beyer, Tilo Abstract: Signal transduction is the process of routing information inside cells when receiving stimuli from their environment that modulate the behavior and function. In such biological processes, the receptors, after receiving the corresponding signals, activate a number of biomolecules which eventually transduce the signal to the nucleus. The main objective of our work is to develop a theoretical approach which will help to better understand the behavior of signal transduction networks due to changes in kinetic parameters and network topology. By using an evolutionary algorithm, we designed a mathematical model which performs basic signaling tasks similar to the signaling process of living cells. We use a simple dynamical model of signaling networks of interacting proteins and their complexes. We study the evolution of signaling networks described by mass-action kinetics. The fitness of the networks is determined by the number of signals detected out of a series of signals with varying strength. The mutations include changes in the reaction rate and network topology. We found that stronger interactions and addition of new nodes lead to improved evolved responses. The strength of the signal does not play any role in determining the response type. This model will help to understand the dynamic behavior of the proteins involved in signaling pathways. It will also help to understand the robustness of the kinetics of the output response upon changes in the rate of reactions and the topology of the network. Sun, 01 Jan 2012 00:00:00 GMT http://hdl.handle.net/10033/267853 2012-01-01T00:00:00Z http://hdl.handle.net/10033/244972 Title: The adapter protein ADAP is required for selected dendritic cell functions. Authors: Togni, Mauro; Engelmann, Swen; Reinhold, Dirk; Schraven, Burkhart; Reinhold, Annegret Abstract: ABSTRACT: Sun, 01 Jan 2012 00:00:00 GMT http://hdl.handle.net/10033/244972 2012-01-01T00:00:00Z http://hdl.handle.net/10033/233572 Title: TCR-mediated Erk activation does not depend on Sos and Grb2 in peripheral human T cells. Authors: Warnecke, Nicole; Poltorak, Mateusz; Kowtharapu, Bhavani S; Arndt, Boerge; Stone, James C; Schraven, Burkhart; Simeoni, Luca Abstract: Sos proteins are ubiquitously expressed activators of Ras. Lymphoid cells also express RasGRP1, another Ras activator. Sos and RasGRP1 are thought to cooperatively control full Ras activation upon T-cell receptor triggering. Using RNA interference, we evaluated whether this mechanism operates in primary human T cells. We found that T-cell antigen receptor (TCR)-mediated Erk activation requires RasGRP1, but not Grb2/Sos. Conversely, Grb2/Sos—but not RasGRP1—are required for IL2-mediated Erk activation. Thus, RasGRP1 and Grb2/Sos are insulators of signals that lead to Ras activation induced by different stimuli, rather than cooperating downstream of the TCR. Sun, 01 Apr 2012 00:00:00 GMT http://hdl.handle.net/10033/233572 2012-04-01T00:00:00Z http://hdl.handle.net/10033/214070 Title: Integrating signals from the T-cell receptor and the interleukin-2 receptor. Authors: Beyer, Tilo; Busse, Mandy; Hristov, Kroum; Gurbiel, Slavyana; Smida, Michal; Haus, Utz-Uwe; Ballerstein, Kathrin; Pfeuffer, Frank; Weismantel, Robert; Schraven, Burkhart; Lindquist, Jonathan A Abstract: T cells orchestrate the adaptive immune response, making them targets for immunotherapy. Although immunosuppressive therapies prevent disease progression, they also leave patients susceptible to opportunistic infections. To identify novel drug targets, we established a logical model describing T-cell receptor (TCR) signaling. However, to have a model that is able to predict new therapeutic approaches, the current drug targets must be included. Therefore, as a next step we generated the interleukin-2 receptor (IL-2R) signaling network and developed a tool to merge logical models. For IL-2R signaling, we show that STAT activation is independent of both Src- and PI3-kinases, while ERK activation depends upon both kinases and additionally requires novel PKCs. In addition, our merged model correctly predicted TCR-induced STAT activation. The combined network also allows information transfer from one receptor to add detail to another, thereby predicting that LAT mediates JNK activation in IL-2R signaling. In summary, the merged model not only enables us to unravel potential cross-talk, but it also suggests new experimental designs and provides a critical step towards designing strategies to reprogram T cells. Mon, 01 Aug 2011 00:00:00 GMT http://hdl.handle.net/10033/214070 2011-08-01T00:00:00Z