Molecular Characterization of GPR56-Induced Human Frontal Cortex Developmental Disease and Tumour Metastasis---A Structural and Functional Analysis of an Adhesion G-Protein Coupled Receptor, GPR56

The LNB-TM7 molecules belong to a subfamily of class B G protein-coupled receptor (GPCR) and are characterized by a novel hybrid structure containing a long N-terminal extracellular domain connected to a 7TM domain by a mucin-like stalk. Based upon their unique structure, it has been suggested that the LNB-TM7 molecules may play a role in the cellular functions by interacting with other cell surface or extracellular matrix proteins, leading to signal transduction via the 7TM domain. Hence, the LNB-TM7 receptors are also named the adhesion-GPCRs. Recent studies have identified a link between the LNB-TM7 receptors and certain human diseases. GPR56, one of the LNB-TM7/adhesion-GPCR members, is recently shown to be solely responsible for a novel human neurological disorder called bilateral frontoparietal polymicrogyria (BFPP). Furthermore, GPR56 is also found to be associated inversely with melanoma metastasis in vivo through the interaction with a cellular ligand, the transglutaminase TG2. The majority of LNB-TM7/adhesion-GPCR receptors are known to undergo a novel post-translational cleavage event at the GPCR proteolytic site (GPS) motif and express on the cell surface as a heterodimeric receptor composed of an extracellular α-subunit and a TM7 β-subunit. We have recently delineated the molecular mechanism of the GPS cleavage and shown that it is a self-catalyzed auto-proteolytic reaction. Interestingly, some of the point mutations found in the GPR56 molecules of BFPP patients are predicted to affect the GPS auto-proteolysis. This research proposal aims to investigate the effect of the BFPP disease-causing point mutations on the structure and function of the GPR56 receptor. In addition, we also propose to identify the brain-specific cellular ligand for GPR56 and to characterize the role of GPR56 in the metastasis of human glioma cells. It is hoped that the results derived from this proposal will provide fundamental clues to the functional role of GPR56 and shed lights on the pathological basis of the human BFPP disease.

Project ID:PC9609-3953
External Project ID:NSC96-2628-B182-030-MY2