Role of membrane protein shrew-1/AJAP1 in epithelial plasticity in vitro and in vivo

粘附动力学的微调是形态上皮可塑性的重要特征，在生理学（例如胚胎发生）以及病理生理学过程（例如癌发展）中是重要的。我们的研究结果表明，膜蛋白shrew-1/AJAP 1作为一种新的调节剂的粘附蛋白E-cadherin内化诱导EGF介导的受体酪氨酸激酶Her 2的激活是高度相关的这些问题。这也适用于新发现的shrew-1/AJAP 1和ezrin（ERM蛋白家族成员）之间的相互作用。ERMs将膜蛋白与细胞骨架连接，并有助于膜受体（例如EGF受体家族）的信号平台的组织，从而影响生长和分化。本研究的主要目的是以乳腺发育为模型系统，在体外和体内研究控制shrew-1/AJAP 1和ezrin之间相互作用的机制，并进一步分析shrew-1/AJAP 1的基因功能。此外，我们对shrew-1/AJAP 1蛋白的结构和功能分析表明，它们具有不同的信号肽，其中两个信号肽引导相同的蛋白。第三个信号肽引导由其胞质结构域组成的shrew-1/AJAP 1的截短版本。在这种情况下，我们的目标是调查a）的区别使用的shrew-1/AJAP 1的信号肽和B）的短shrew-1/AJAP 1亚型的功能。

The fine tuning of adhesion dynamics is a central feature of morphological epithelial plasticity impor-tant in physiological (e.g. embryogenesis) as well as in pathophysiological processes (e.g. carcinoma development). Our findings that membrane protein shrew-1/AJAP1 acts as a novel modulator of adhe-sion protein E-cadherin internalization induced by EGF-mediated activation of receptor tyrosine kinase Her2 are highly relevant for these issues. This is also true for the newly discovered interplay between shrew-1/AJAP1 and ezrin, a member of the ERM protein family. ERMs link membrane proteins with the cytoskeleton and contribute to the organization of signalling platforms for membrane receptors (e.g. EGF receptor family) thereby influencing growth and differentiation. Deciphering mechanism(s) controlling the interplay between shrew-1/AJAP1 and ezrin as well as further analysis of shrew-1/AJAP1’s gene function using mammary gland development as a model system in vitro and in vivo are central aims of this proposal. Furthermore, our structure function analyses of shrew-1/AJAP1 pro-tein revealed different signal peptides, two of which lead the same protein. The third signal peptide guides a truncated version of shrew-1/AJAP1 composed of its cytoplasmic domain. In this context we aim to investigate a) the differential use of shrew-1/AJAP1’s signal peptides and b) the function of the short shrew-1/AJAP1 isoform.