Regulation of cell polarity and tight junction formation in vertebrate epithelial and endothelial cells by cell adhesion receptors

直到最近，人们对脊椎动物上皮细胞和内皮细胞中调节紧密连接（TJ）形成和膜极性的分子知之甚少。最近发现的一种多组分信号复合物，包括PDZ结构域的支架蛋白（PAR-3，PAR-6）和信号转导蛋白（aPKC，Cdc 42）引起了细胞极性领域的广泛关注。该复合物在进化过程中是保守的，并且似乎是上皮细胞中紧密连接的形成和/或维持所需的。与JAM-1，我们已经确定了第一个跨膜组件在TJ与PAR-3。我们的研究旨在更详细地了解JAM-1在TJ形成中的功能。具体目标是：（1）分析PAR-3与JAM的结合是否是a）PAR-3募集到细胞间接触和B）上皮细胞中紧密连接形成所必需的;（2）分析涉及JAM和TJ蛋白ZO家族成员的蛋白质复合物（ZO-1、ZO-2和ZO-3）;和（3）分析肝细胞生长因子是否通过作用于JAM-1的TJ定位来影响TJ完整性。

Until recently, little was known about the molecules regulating the formation of tight junctions (TJ) and membrane polarity in vertebrate epithelial and endothelial cells. The recent discovery of a multicomponent signalling complex consisting of PDZ domain-containing scaffolding proteins (PAR-3, PAR-6) and signal transducing proteins (aPKC, Cdc42) has attracted much attention in the field of cell polarity. This complex is conserved through evolution and seems to be required for the formation and/or maintenance of tight junctions in epithelial cells. With JAM-1 we have identified the first transmembrane component in TJs which associates with PAR-3. Our studies aim at a more detailed understanding of the function of JAM-1 in the formation of TJs. The specific aims are: (1) to analyze if the association of PAR-3 with JAM is required for a) the recruitment of PAR-3 to intercellular contacts and b) the formation of tight junctions in epithelial cells; (2) to analyze protein complexes involving JAMs and members of the ZO family of TJ proteins (ZO-1, ZO-2, and ZO-3); and (3) to analyze if Hepatocyte Growth Factor affects TJ integrity by acting on the TJ localization of JAM-1.