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

Met受体信号转导的分子机制：配体InIB的激活和CD44v6的共受体功能

• 批准号: 187647894
• 负责人: Professor Dr. Mike Heilemann
• 金额: --
• 依托单位: Institut für Physikalische und Theoretische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/187647894?language=en
• 关键词: Molecular; mechanism; signal; transduction; through

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.

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起着重要作用。此外，一些病原体在感染过程中靶向Met。单核增生李斯特菌利用表面蛋白InlB激活Met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激活所必需的共受体。虽然CD44v6对HGF和InlB活化Met的重要性已得到证实，但CD44v6的作用机制尚不清楚。在此，我们拟研究Met被其配体HGF和InlB激活的分子机制，重点研究其共受体CD44v6的功能。我们想通过体外结合实验来测试CD44v6是否直接与InlB和HGF或Met相互作用。CD44v6与配体和/或受体的二元或三元配合物的结构将通过x射线晶体学进行研究。此外，我们希望利用单分子和超分辨率荧光方法研究CD44v6对配体诱导的受体二聚化和受体内化在细胞中的影响。