Research Group Signal Transduction

Research Objectives

The signal transduction group investigates the molecular basis of cell transformation by the latent membrane protein 1 (LMP1), the primary oncogene of EBV. We focus at elucidating the molecular interactions of LMP1 with cellular signaling pathways to define LMP1’s contribution to chronic disease development by EBV infection. Novel molecular players are identified by proteomic analysis of the LMP1 signalosome. Because LMP1 has developed to a powerful transforming protein during virus evolution, we hypothesize that cellular molecules and pathways exploited by LMP1 play central roles in physiological regulation of cell survival and proliferation. By comparing the functions of critical factors in signaling by LMP1 and related cellular receptors such as TNF-receptor or CD40, we want to understand basic principles of cell regulation and lymphocyte homeostasis and their deregulation by viral oncoproteins. Finally, we aim at developing specific small molecule inhibitors of LMP1 signaling and, thus, EBV-induced malignancies.

LMP1 serves as proto-type of a viral pseudoreceptor that usurps host cellular signal transduction to reprogram its target cell. Through its two cytoplasmic CTAR subdomains 1 and 2, LMP1 recruits signaling proteins derived from the target cell to control cellular proliferation and survival. Thereby, it mimics functions of the co-stimulatory CD40 receptor on B-cells. Among the directly recruited signaling proteins are TRAF proteins and TRADD which are required for LMP1 to induce NF-κB, JNK, MAPK and PI3-kinase signaling (see Figure).

Model of LMP1 signal transduction

We are especially interested in immediate and direct signaling events of LMP1 and related receptors that are involved in the decision-making processes proximal to the receptor. To this end, we approach LMP1 signaling at two levels: 1) We study the molecular functions of already known components of the LMP1 signalosome interaction partners and signaling pathways. 2) We established unbiased proteomics approaches to identify new components of the LMP1 signalosome. Novel interaction partners such as the germinal center kinase TNIK are further characterized. Our studies on TNIK revealed a central role for TNIK in TRAF6-dependent JNK and NF-κB signaling not only in LMP1 but also in physiological CD40 signaling in B-cells. We want learn more about lymphocyte homeostasis and function in vivo by studying physiological roles of LMP1 signaling mediators such as TNIK in mouse models. To translate the results of our basic research into an application we follow the concept that the interface between viral oncoproteins such as LMP1 and cellular regulatory factors constitute feasible, unique and, thus, specific targets for small molecule inhibitors.

See here for a more specific description of our research projects.