Blood vessels and nerves follow the same patterning during embryogenesis and often run in parallel in the tissues. There are several examples of protein families that play roles in both vessel and nerve functions. One such example is the family of Eph receptors and ephrin ligands, which serve important functions by providing spatial cues for the development of both nervous and vascular systems. One peculiarity that makes this system unique among the RTK family is that the ligands also possess signaling capabilities, a feature known as 'reverse signaling'.

In our group we are interested in molecularly dissecting the signaling pathways activated downstream of ephrinB ligands. Our main focus in the nervous system is to study the role of Eph receptors and ephrinB ligands at the synapse, both at molecular as well as at a functional level. In addition, we are also elucidating for example the crosstalk between ephrin signaling and other signaling pathways important for neuronal migration. In the vasculature we are particularly interested in studying communication between endothelial cells during vessel homeostasis as well as communication between endothelial cells and tumor cells in the brain during tumor invasion and metastasis.

To study the influence of the Eph/ephrin system in the nervous and vascular systems, we employ different cellular models including rat and mice primary cortical and hippocampal neurons as well as primary endothelial cells. As an animal model we use the mouse, including different transgenic as well as genetically modified mouse lines. We use a broad range of biochemical and cell biology methods. We also use innovative techniques like time lapse imaging for the study of cell adhesion/repulsion induced by Eph and ephrin signaling in both neurons and blood vessels. Moreover, our laboratory has successfully applied the proteomic technology (TAP) in the mammalian system, both in primary cells and in transgenic mice.

Early steps in ephrinB reverse signaling involve phosphorylation on tyrosine residues and interaction with PDZ proteins via its carboxy-terminal tail. Our work has identified Src family kinases (SFKs) as positive regulators of ephrinB phosphorylation and ephrinB-mediated angiogenic sprouting of primary endothelial cells (Palmer et al., 2002). Stimulation with EphB receptors induces the formation of large patches in the membrane containing ephrinB ligands and Src. We have also identified the PDZ domain containing phosphatase PTP-BL as an important component of the signaling apparatus downstream ephrinB ligands. Based on our data we propose the presence of a switch mechanism that allows a shift from phosphotyrosine/SFK-dependent reverse signaling to PDZ-dependent reverse signaling.

Another important contribution of our studies has been the identification of endocytosis of EphB-ephrinB complexes as a novel mechanism for termination of adhesion and promotion of cell repulsion after intercellular (trans) interaction between two transmembrane proteins. Endocytosis occurs in a bi-directional manner and comprises complexes of full-length receptor and ligand (Zimmer et al., 2003) . A challenging question is now to understand the unresolved issue of how the choice between Eph-ephrin-mediated contact repulsion and stable adhesion is made in vivo at the molecular level.

Postsynaptic ephrinB reverse signaling is required for the process of synaptic plasticity at the CA3-CA1 synapse. However, the precise function of ephrins in the initiation of intracellular signals at the mature synapse as well as the molecular mechanism underlying the plasticity functions of ephrinBs remained so far unknown. We have  mapped the molecular pathway downstream of ephrinB ligands that is required for proper spine morphogenesis and synapse formation (Segura et al., 2007). Plasticity in the brain is essential for maintaining memory and learning and is associated with the dynamic membrane trafficking of AMPA receptors. We have recently described a molecular mechanism for ephrinB2 function in controlling synaptic transmission. EphrinB2 signaling is critical for the stabilization of AMPA receptors at the cellular membrane (Essmann et al., 2008).




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Druckversion: 22. Mai 2009, 08:20