Project 05

The role of the Adhesion G protein-coupled receptor GPR133/ADGRD1 in the mechano-sensitive tissues heart and bone

Ines Liebscher, Leipzig University 

Team members
Caroline Wilde

Project Description
Identifying the activation mechanism of adhesion G protein-coupled receptors (aGPCRs) has been the main goal of this project. We were able to define a tethered agonist region, establish derived agonistic and antagonistic peptides and showed one possible way to achieve aGPCR activation in vivo and in vitro through an orchestrated sequence including binding of an extracellular interaction partner, mechanical force and tethered agonist-mediated activation of intracellular signaling cascades. We now aim to translate these findings into the characterization of the consequences of the deletion of an orphan aGPCR, the GPR133/ADGRD1 in zebrafish and mice in tissues that are known to respond to or work through mechanical forces, bone and heart.

Publications

Favara DM, Liebscher I, Jazayeri A, Nambiar M, Sheldon H, Banham AH, Harris AL (2021) Elevated expression of the adhesion GPCR ADGRL4/ELTD1 promotes endothelial sprouting angiogenesis without activating canonical GPCR signalling. Sci Rep. 11(1): 8870. 

Frenster JD, Stephan G, Ravn-Boess N, Bready D, Wilcox J, Kieslich B, Wilde C, Sträter N, Wiggin GR, Liebscher I , Schöneberg TPlacantonakis DG (2021) Functional impact of intramolecular cleavage and dissociation of adhesion G protein-coupled receptor GPR133 (ADGRD1) on canonical signaling. J Biol Chem. 100798. Online ahead of print. 

Schöneberg TLiebscher I (2021) Mutations in G Protein-Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches. Pharmacol Rev. 73: 89-119. 

Suchý T, Zieschang C, Popkova Y, Kaczmarek I, Weiner J, Liebing AD, Çakir MV, Landgraf K, Gericke M, Pospisilik JA, Körner A, Heiker JT, Dannenberger D, Schiller J, Schöneberg TLiebscher I, Thor D (2020) The repertoire of Adhesion G protein-coupled receptors in adipocytes and their functional relevance. Int J Obes (Lond). doi: 10.1038/s41366-020-0570-2. [Epub ahead of print]. 

Bradley EC, Cunningham RL, Wilde C, Morgan RK, Klug EA, Letcher SM, Schöneberg T, Monk KR, Liebscher I, Petersen SC (2019) In vivo identification of small molecules mediating Gpr126/Adgrg6 signaling during Schwann cell development. Annals of the New York Academy of Sciences doi: 10.1111/nyas.14233. [Epub ahead of print]. 

Eichler W, Lohrenz A, Simon KU, Krohn S, Lange J, Bürger S, Liebscher I (2019) The role of ADGRE5/CD97 in human retinal pigment epithelial cell growth and survival. Annals of the New York Academy of Sciences. doi: 10.1111/nyas.14210. [Epub ahead of print]. 

Knierim AB, Röthe J, Çakir MV, Lede V, Wilde C, Liebscher I, Thor D, Schöneberg T. Genetic basis of functional variability in adhesion G protein-coupled receptors. Sci Rep. 2019; 9:11036. 

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 SScholz 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] 

Hilbig D, Sittig D, Hoffmann F, Rothemund S, Warmt E, Quaas M, Stürmer J, Seiler L, Liebscher I, Hoang NA, Käs JA, Banks L, Aust G (2018) Mechano-Dependent Phosphorylation of the PDZ-Binding Motif of CD97/ADGRE5 Modulates Cellular Detachment. Cell Rep. 24: 1986-1995. 

Hsiao CC, Chu TY, Wu CJ, van den Biggelaar M, Pabst C, Hébert J, Kuijpers TW, Scicluna BP, I KY, Chen TC, Liebscher IHamann J, Lin HH (2018) The Adhesion G Protein-Coupled Receptor GPR97/ADGRG3 Is Expressed in Human Granulocytes and Triggers Antimicrobial Effector Functions. Frontiers in Immunology. 9:2830. fimmu.2018.02830. eCollection.