Molecular mechanism of signal transduction through the Met receptor: Activation by the ligand InIB and co-receptor function of CD44v6

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The human receptor tyrosine kinase Met and its ligand HGF are essential during embryonic development. They also play an important role during cancer metastasis and in tissue regeneration. Moreover, several pathogens target Met during infection. The bacterium Listeria monocytogenes uses the surface protein InlB that activates Met in order to induce bacterial uptake. Studies on cells and in animals revealed that CD44v6, a splice variant of the transmembrane protein CD44, is a co-receptor essential for Met activation. While the importance of CD44v6 for Met activation by HGF and InlB is well established, the mechanism by which CD44v6 acts is still unclear. Here, we propose to study the molecular mechanism of Met activation by its ligands HGF and InlB with an emphasis on the function of the co-receptor CD44v6. We want to test whether CD44v6 directly interacts with InlB and HGF or with Met using in vitro binding experiments. The structure of binary or ternary complexes of CD44v6 with ligands and/or the receptor will be investigated by X-ray crystallography. In addition, we want to use single-molecule and super-resolution fluorescence methods to study the influence of CD44v6 on ligand-induced receptor dimerization and receptor internalization in cells.