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

项目描述（由申请人提供）：“与癌症相关的黏附gpcr结构-功能研究平台”项目重点研究黏附gpcr，这是第二大g蛋白偶联受体（gpcr）家族。这些受体通过控制细胞间相互作用以及细胞内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。它们的重要性，作为新的癌症治疗靶点，是有据可查的，它们被认为是特定类型癌症的生物标志物。然而，粘附GPCR也是最不为人所知的GPCR家族。由于纯化样品的生产困难，结构和功能/生化研究受到限制或几乎不存在。蛋白质的结构信息是了解其分子活性和功能机制的重要资源，也是设计特异性治疗方法的重要工具，使其成为药物开发的重要工具。在这里，我们建议通过聚焦于一个成员CD97受体来开启粘附gpcr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、食管癌、胰腺癌、结直肠癌等的进展，因此被认为是一个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构建体建立基础，用于结晶和生化表征，其中包括使用抗体。本研究的结果将：1)为功能研究提供CD97的数量，2)确定第一个粘附GPCR的结构，3)为进一步研究整个粘附GPCR家族提供平台。因此，本研究将为更全面的粘附gpcr研究奠定基础，以了解其如何调节癌症的发生和进展，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.