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

人类受体酪氨酸激酶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发挥着重要作用。此外，几种病原体在感染期间以蛋氨酸为靶标。单核细胞增生性李斯特菌使用表面蛋白InlB来激活蛋氨酸，以诱导细菌摄取。对细胞和动物的研究表明，CD44v6是跨膜蛋白CD44的剪接变体，是Met激活所必需的辅助受体。虽然CD44v6在HGF和In1B激活Met中的重要性已被证实，但CD44v6的作用机制仍不清楚。在这里，我们建议研究其配体HGF和In1B激活Met的分子机制，重点是协同受体CD44v6的功能。我们希望通过体外结合实验来测试CD44v6是直接与In1B和HGF相互作用，还是与Met相互作用。CD44v6与配体和/或受体的二元或三元络合物的结构将通过X射线结晶学进行研究。此外，我们还想用单分子和超分辨荧光方法来研究CD44v6对细胞内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.