VLGR1 signaling at focal adhesions and ICD release as a non-canonical signaling pathway of aGPCRs

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VLGR1 (very large G protein-coupled receptor-1), also known asADGRV1, GPR98 and MASS is by far the largest adhesion GPCR(aGPCR). Although VLGR1 expression is almost ubiquitous, it ishighly concentrated in the nervous system. Mutations in the humanVLGR1 gene cause the human Usher syndrome (USH), the mostcommon form of hereditary deaf-blindness. In addition, there isgrowing evidence that defects in VLGR1 are also associated withepilepsy. So far, little is known about its dual function in membranemembraneadhesion and signaling. In the current funding period, weidentified interaction partners and protein clusters related to VLGR1,and to several other aGPCRs by applying affinity proteomics (tandemaffinity purifications (TAPs) in combination with mass spec).Bioinformatics analyses of the interactomes of these aGPCRs havedefined Gene Ontology (GO) terms and cell modules related toputative aGPCR function. For the second grant period, we haveselected specific functional modules for further evaluation and indepthcharacterization of their signaling function for VLGR1 and foraGPCRs. (1) We will elucidate the role of VLGR1 in focal adhesions(FAs) which act as signaling hubs between the ECM and the actincytoskeleton essential for cell outgrowth and migration. We will testVLGR1´s contribution to the spatial and temporal control of FAturnover, the regulation of cell migration and the modulation of thecytoskeleton using divers VLGR1 deficient cellular models includingdifferent types of neural cell. (2) We will decipher the interaction ofVLGR1 and other aGPCRs with the gamma-secretase complex as acommon non-canonical aGPCR signaling pathway. For this, we willtest whether aGPCRs are substrates of the gamma-secretase andhow their intracellular domains (ICDs) are released into thecytoplasm. Furthermore, we will evaluate nuclear functions ofaGPCRs. We are certain that our results will help to understand howaGPCRs work. We also hope to gain new insights into thepathomechanisms of diseases associated with the dysfunction ofaGPCRs and see opportunities to identify new therapeutic targets forthe treatment of these diseases.