VLGR1 signaling at focal adhesions and ICD release as a non-canonical signaling pathway of aGPCRs
Uwe Wolfrum, University of Mainz
Deva K. Kusuluri
VLGR1 (very large G protein-coupled receptor-1), also known as ADGRV1, GPR98 and MASS is by far the largest adhesion GPCR (aGPCR). Although VLGR1 expression is almost ubiquitous, it is highly concentrated in the nervous system. Mutations in the human VLGR1 gene cause the human Usher syndrome (USH), the most common form of hereditary deaf-blindness. In addition, there is growing evidence that defects in VLGR1 are also associated with epilepsy. So far, little is known about its dual function in membrane-membrane adhesion and signaling. In the current funding period, we identified interaction partners and protein clusters related to VLGR1, and to several other aGPCRs by applying affinity proteomics (tandem affinity purifications (TAPs) in combination with mass spec). Bioinformatics analyses of the interactomes of these aGPCRs have defined Gene Ontology (GO) terms and cell modules related to putative aGPCR function.
(2) We will decipher the interaction of VLGR1 and other aGPCRs with the gamma-secretase complex as a common non-canonical aGPCR signaling pathway. For this, we will test whether aGPCRs are substrates of the gamma-secretase and how their intracellular domains (ICDs) are released into the cytoplasm. Furthermore, we will evaluate nuclear functions of aGPCRs.
We are certain that our results will help to understand how aGPCRs work. We also hope to gain new insights into the pathomechanisms of diseases associated with the dysfunction of aGPCRs and see opportunities to identify new therapeutic targets for the treatment of these diseases.
Morgan RK, Anderson GR, Araç D, Aust G, Balenga N, Boucard A, Bridges JP, Engel FB, Formstone CJ, Glitsch MD, Gray RS, Hall RA, Hsiao CC, Kim HY, Knierim AB, Kusuluri DK, Leon K, Liebscher I, Piao X, Prömel S, Scholz N, Srivastava S,Thor D, Tolias KF, Ushkaryov YA, Vallon M, Van Meir EG, Vanhollebeke B, Wolfrum U, Wright KM, Monk KR, Mogha A (2019). The expanding functional roles and signaling mechanisms of adhesion G protein-coupled receptors. Annals of the New York Academy of Sciences. doi: 10.1111/nyas.14094. [Epub ahead of print]