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

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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.