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

人受体酪氨酸激酶Met及其配体HGF在胚胎发育过程中是必不可少的。它们在癌症转移和组织再生过程中也起重要作用。此外，几种病原体在感染期间靶向Met。细菌单核细胞增生李斯特菌使用激活Met的表面蛋白InlB以诱导细菌摄取。对细胞和动物的研究表明，跨膜蛋白CD 44的剪接变体CD 44 v6是Met活化所必需的共受体。虽然CD 44 v6对于HGF和InlB激活Met的重要性已得到充分证实，但CD 44 v6的作用机制仍不清楚。 在这里，我们建议研究其配体HGF和InlB激活Met的分子机制，重点是共受体CD 44 v6的功能。我们想要使用体外结合实验来测试CD 44 v6是否直接与InlB和HGF或与Met相互作用。将通过X射线晶体学研究CD 44 v6与配体和/或受体的二元或三元复合物的结构。此外，我们还想利用单分子和超分辨荧光技术研究CD 44 v6对配体诱导的受体二聚化和受体内化的影响。

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.