http://hdl.handle.net/10033/214050 Leiter: Prof Dr. B. Schraven Mon, 20 May 2013 12:02:59 GMT 2013-05-20T12:02:59Z http://hdl.handle.net/10033/288580 Title: Atypical IκB proteins - nuclear modulators of NF-κB signaling. Authors: Schuster, Marc; Annemann, Michaela; Plaza-Sirvent, Carlos; Schmitz, Ingo Abstract: Nuclear factor κB (NF-κB) controls a multitude of physiological processes such as cell differentiation, cytokine expression, survival and proliferation. Since NF-κB governs embryogenesis, tissue homeostasis and the functions of innate and adaptive immune cells it represents one of the most important and versatile signaling networks known. Its activity is regulated via the inhibitors of NF-κB signaling, the IκB proteins. Classical IκBs, like the prototypical protein IκBα, sequester NF-κB transcription factors in the cytoplasm by masking of their nuclear localization signals (NLS). Thus, binding of NF-κB to the DNA is inhibited. The accessibility of the NLS is controlled via the degradation of IκBα. Phosphorylation of the conserved serine residues 32 and 36 leads to polyubiquitination and subsequent proteasomal degradation. This process marks the central event of canonical NF-κB activation. Once their NLS is accessible, NF-κB transcription factors translocate into the nucleus, bind to the DNA and regulate the transcription of their respective target genes. Several studies described a distinct group of atypical IκB proteins, referred to as the BCL-3 subfamily. Those atypical IκBs show entirely different sub-cellular localizations, activation kinetics and an unexpected functional diversity. First of all, their interaction with NF-κB transcription factors takes place in the nucleus in contrast to classical IκBs, whose binding to NF-κB predominantly occurs in the cytoplasm. Secondly, atypical IκBs are strongly induced after NF-κB activation, for example by LPS and IL-1β stimulation or triggering of B cell and T cell antigen receptors, but are not degraded in the first place like their conventional relatives. Finally, the interaction of atypical IκBs with DNA-associated NF-κB transcription factors can further enhance or diminish their transcriptional activity. Thus, they do not exclusively act as inhibitors of NF-κB activity. The capacity to modulate NF-κB transcription either positively or negatively, represents their most important and unique mechanistic difference to classical IκBs. Several reports revealed the importance of atypical IκB proteins for immune homeostasis and the severe consequences following their loss of function. This review summarizes insights into the physiological processes regulated by this protein class and the relevance of atypical IκB functioning. Tue, 01 Jan 2013 00:00:00 GMT http://hdl.handle.net/10033/288580 2013-01-01T00:00:00Z 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