Platform for Structure-Function Studies of Adhesion GPCRs implicated in Cancer

描述(申请人提供)：“肿瘤相关粘附性GPCRs结构与功能研究平台”项目致力于为研究粘附性GPCRs奠定基础，粘附性GPCRs是G蛋白偶联受体的第二大家族。这些受体通过控制细胞间的相互作用以及细胞内的信号传导来调节细胞的迁移和发育，这使得它们在肿瘤发生和癌症进展中发挥着至关重要的作用。它们作为新的癌症治疗靶点的重要性得到了很好的证明，它们被认为是特定类型癌症的生物标记物。然而，粘附性GPCRs也是最不被理解的GPCRs家族。由于生产纯化样品的困难，结构和功能/生化研究一直有限或几乎不存在。蛋白质的结构信息是了解其分子活性和作用机制以及设计特定治疗药物的强大资源，使其成为药物开发的关键工具。在这里，我们建议通过关注一个成员CD97受体来启动粘附性GPCRs成员的结构确定之路。CD97是表皮生长因子(EGF)受体家族的一员，参与甲状腺、乳腺癌、胃癌、食道癌、胰腺癌、结直肠癌等多种肿瘤的发生发展，是一种直接的肿瘤抑制靶点。我们的目标是为大规模生产稳定的CD97构建体奠定基础，用于结晶和生化表征，包括使用抗体。拟议的研究结果将：1)为功能研究提供大量的CD97，2)能够确定第一个粘附性GPCR的结构，3)为进一步研究整个粘附性GPCR家族提供平台。因此，这项研究将为更全面地研究粘附性GPCRs奠定基础，以了解它们如何调控癌症的发生和发展，并为设计新药提供基础。

DESCRIPTION (provided by applicant): The project "Platform for Structure-Function Studies of Adhesion GPCRs implicated in Cancer" focuses on establishing the essential basis for studying adhesion GPCRs, which are the second largest family of G-protein coupled receptors (GPCRs). These receptors regulate the migration and development of cells by controlling cell-cell interactions, as well as the intracellular signaling, which makes them of utmost importance because of their roles in tumorigenesis and cancer progression. Their importance, as novel cancer therapeutic targets, is well documented and they are considered biomarkers for specific types of cancers. However, adhesion GPCRs are also the least understood GPCR family. Structural and functional/biochemical studies have been limited or almost non-existent due to difficulties in producing purified samples. Structural information of proteins is a powerful resource for understanding their molecular activities and mechanisms of function, as well as for designing specific therapeutics making them key tools for drug development. Here, we propose to initiate the road to structural determination for members of adhesion GPCRs, by focusing on one member, CD97 receptor. CD97 is a member of the epidermal growth factor (EGF) receptor family involved in progression of thyroid, breast, gastric, esophageal, pancreatic, colorectal cancers, etc. and thus has been suggested as a direct tumor suppressor target. We aim to establish the basis for large-scale production of stabilized CD97 constructs for crystallization and biochemical characterization, which include the use of antibodies. The outcome of the proposed study will: 1) provide quantities of CD97 for functional studies, 2) enable the determination of the structure of the first adhesion GPCR, and 3) provide a platform for further studies of the entire adhesion GPCR family. Thus, this study will set the essentials for more comprehensive studies of adhesion GPCRs towards understanding how they regulate cancer development and progression and provide a basis for designing new drugs.