Project B05 – Signal integration and specification of adhesion GPCRs
Project B05 wants to investigate, which specific intracellular signaling pathways of an adhesion GPCR are activated by different stimuli. Based on the observation that N-terminal ligands of the adhesion GPCR GPR126/ADGRG6 can induce a Gs/Gi-preference in signal transduction we aim to decipher the complex intracellular cascades that result from this G protein bias including the engagement of so far unknown non-canonical signals mediated by different kinases and arrestins. We will study the signaling preferences of a whole subset of activators that we established in the first funding period. To tackle this endeavour, we will employ a combination of classic biochemical methods such as co-immunoprecipitation and Western blotting as well as conformational biosensors and reporter assays. We further aim to identify the structural basis of signaling bias on GPR126/ADGRG6 for which we will tightly collaborate with experts in structural biology and computational modelling within the CRC.
Structural consequences of adhesion GPCR activation
This project aims to elucidate how mechanical force, extracellular interaction partners and the tethered agonist interplay in a concerted sequence to induce the active state of adhesion GPCRs. We will fill the gap between available functional and structural data by adding new structural information using basic biochemical approaches (cross linking, Western Blot, ELISA), Fluorescence Resonance Energy Transfer (FRET) techniques and electron paramagnetic resonance (EPR). We will identify and compare different forms of mechanical forces that are sufficient for aGPCR activation and we will study the structural changes of the N terminus, the Stachel sequence and the 7TM upon peptide and mechanical force application.
Contact
Prof. Dr. Dr. Ines Liebscher (Project Leader)
Leipzig University, Faculty of Medicine
Rudolf Schönheimer Institute of Biochemistry
Johannisallee 30, D-04103 Leipzig
Phone +49 341 97 22141
E-Mail
Web https://www.uniklinikum-leipzig.de/signaltransduktion/ag-liebscher
Luisa Buhl (PhD, Doctoral Representative)
Leipzig University, Faculty of Medicine
Rudolf Schönheimer Institute of Biochemistry
Johannisallee 30, D-04103 Leipzig
Resources
- Cross Linking, Western Blot & ELISA
- Fluorescence Resonance Energy Transfer (FRET) techniques and
- electron paramagnetic resonance (EPR)
Publications
Kuhn CK, Stenzel U, Berndt S, Liebscher I, Schöneberg T, Horn S. The repertoire and structure of adhesion GPCR transcript variants assembled from publicly available deep-sequenced human samples. Nucleic Acids Res. 2024 Feb 29:gkae145. doi: 10.1093/nar/gkae145 .
Röthe J, Kraft R, Ricken A, Kaczmarek I, Matz-Soja M, Winter K, Dietzsch AN, Buchold J, Ludwig MG, Liebscher I, Schöneberg T, Thor D. The adhesion GPCR GPR116/ADGRF5 has a dual function in pancreatic islets regulating somatostatin release and islet development. Commun Biol. 2024 Jan 16;7(1):104.
Scharf MM, Humphrys LJ, Berndt S, Di Pizio A, Lehmann J, Liebscher I, Nicoli A, Niv MY, Peri L, Schihada H, Schulte G. The dark sides of the GPCR tree – research progress on understudied GPCRs. Br J Pharmacol. 2024 Feb 10. doi: 10.1111/bph.16325 .
Beer-Hammer S, Liebscher I. G Protein-Coupled Receptors in Cell Signaling Transduction. Int J Mol Sci. 2023 Dec 25;25(1):291.
Frenster JD, Erdjument-Bromage H, Liu W, Stephan G, Ravn-Boess N, Bready D, Wilcox J, Kieslich B, Jankovic M, Wilde C, Horn S, Sträter N, Liebscher I, Schöneberg T, Fenyo D, Neubert TA, Placantonakis DG. PTK7 is a positive allosteric modulator of GPR133 (ADGRD1) signaling in GBM. biorxiv. 2022.06. 15.496232.
Knapp B, Roedig J, Roedig H, Krzysko J, Horn N, Güler BE, Kusuluri DK, Yildirim A, Boldt K, Ueffing M, Liebscher I, Wolfrum U. Affinity Proteomics Identifies Interaction Partners and Defines Novel Insights into the Function of the Adhesion GPCR VLGR1/ADGRV1. Molecules. 2022; 27:3108.
Liebscher I, Schöneberg T, Thor D. Stachel-mediated activation of adhesion G protein-coupled receptors: insights from cryo-EM studies. Signal Transduct Target Ther. 2022 Jul 9;7(1):227. doi: 10.1038/s41392-022-01083-y. PMID: 35810167.
Mitgau J, Franke J, Schinner C, Stephan G, Berndt S, Placantonakis DG, Kalwa H, Spindler V, Wilde C, Liebscher I. The N Terminus of Adhesion G Protein-Coupled Receptor GPR126/ADGRG6 as Allosteric Force Integrator. Front Cell Dev Biol. 2022 Jun 23;10:873278. doi: 10.3389/fcell.2022.873278. eCollection 2022. PMID: 35813217.
Ping YQ, Xiao P, Yang F, Zhao RJ, Guo SC, Yan X, Wu X, Zhang C, Lu Y, Zhao F, Zhou F, Xi YT, Yin W, Liu FZ, He DF, Zhang DL, Zhu ZL, Jiang Y, Du L, Feng SQ, Schöneberg T, Liebscher I, Xu HE, Sun JP. Structural basis for the tethered peptide activation of adhesion GPCRs. Nature. 2022. https://doi.org/10.1038/s41586-022-04619-y.
Stephan G, Frenster JD, Liebscher I, Placantonakis DG. Activation of the adhesion G protein-coupled receptor GPR133 (ADGRD1) by antibodies targeting its N-terminus. J Biol Chem. 2022 Apr 18:101949. doi: 10.1016/j.jbc.2022.101949. Online ahead of print. PMID: 35447113
Wilde C, Mitgau J, Suchý T, Schoeneberg T, Liebscher I. Translating the Force – mechano-sensing GPCRs. Am J Physiol Cell Physiol. 2022 Apr 13. doi: 10.1152/ajpcell.00465.2021. Online ahead of print. PMID: 35417266 Review.
Berndt S, Liebscher I. New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation. Int J Mol Sci. 2021 Jun 17;22(12):6489. doi: 10.3390/ijms22126489. PMID: 34204297; PMCID: PMC8233884.
Favara DM, Liebscher I, Jazayeri A, Nambiar M, Sheldon H, Banham AH, Harris AL. Elevated expression of the adhesion GPCR ADGRL4/ELTD1 promotes endothelial sprouting angiogenesis without activating canonical GPCR signaling. Sci Rep. 2021; 11:8870.
Frenster JD, Stephan G, Ravn-Boess N, Bready D, Wilcox J, Kieslich B, Wilde C, Sträter N, Wiggin GR, Liebscher I, Schöneberg T, Placantonakis DG. Functional impact of intramolecular cleavage and dissociation of adhesion G protein-coupled receptor GPR133 (ADGRD1) on canonical signaling. J Biol Chem. 2021 May 19:100798. doi: 10.1016/j.jbc.2021.100798. Epub ahead of print. PMID: 34022221.
Liebscher I, Cevheroğlu O, Hsiao CC, Maia AF, Schihada H, Scholz N, Soave M, Spiess K, Trajković K, Kosloff M, Prömel S. A Guide to Adhesion GPCR research. FEBS J. 2021 Nov 2. doi: 10.1111/febs.16258. Epub ahead of print. PMID: 34729908.
Schöneberg T, Liebscher I. Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches. Pharamcological Reviews. 2021; 73:89-119. doi: https://doi.org/10.1124/pharmrev.120.000011.
Suchý T, Kaczmarek I, Maricic T, Zieschang C, Schöneberg T, Thor D, Liebscher I. Evaluating the feasibility of Cas9 overexpression in 3T3-L1 cells for generation of genetic knock-out adipocyte cell lines. Adipocyte. 2021 Dec;10(1):631-645. doi: 10.1080/21623945.2021.1990480. PMID:
34915813.
None.
Mogha A, Benesh AE, Patra C, Engel FB, Schöneberg T, Liebscher I, Monk KR. Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation. J Neurosci. 2013; 33:17976-85.
Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin HH, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, Schiöth HB. International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol Rev. 2015; 67:338-67.
Liebscher I*, Schön J*, Petersen SC, Fischer L, Auerbach N, Demberg LM, Mogha A, Cöster M, Simon KU, Rothemund S,Monk KR, Schöneberg T. A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133. Cell Rep. 2014; 9:2018-26.
Demberg LM, Rothemund S, Schöneberg T, Liebscher I. Identification of the tethered peptide agonist of the adhesion G protein-coupled receptor GPR64/ADGRG2. 2015; 464:743-7.
Wilde C, Fischer L, Lede V, Kirchberger J, Rothemund S, Schöneberg T, Liebscher I. The constitutive activity of the adhesion GPCR GPR114/ADGRG5 is mediated by its tethered agonist. FASEB J. 2016; 30:666-73.
Demberg LM, Winkler J, Wilde C, Simon KU, Schön J, Rothemund S, Schöneberg T, Prömel S*, Liebscher I*. Activation of adhesion G protein-coupled receptors: agonist specificity of Stachel sequence-derived peptides. J Biol Chem. 2017; 292:4383-94.
Hsiao CC, Chu TY, Wu CJ, van den Biggelaar M, Pabst C, Hébert J, Kuijpers TW, Scicluna BP, I KY, Chen TC, Liebscher I, Hamann J, Lin HH. The adhesion G protein-coupled receptor GPR97/ADGRG3 is expressed in human granulocytes and triggers antimicrobial effector functions. Front Immunol. 2018; 9:2830.
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. Mechano-Dependent Phosphorylation of the PDZ-Binding Motif of CD97/ADGRE5 Modulates Cellular Detachment. Cell Rep. 2018; 24:1986-95.
Petersen SC*, Luo R*, Liebscher I*, Giera S, Jeong SJ, Mogha A, Ghidinelli M, Feltri ML, Schöneberg T, Piao X, Monk KR. The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211. Neuron. 2015; 85:755-69.
Monk KR, Hamann J, Langenhan T, Nijmeijer S, Schöneberg T, Liebscher I. Adhesion G Protein-Coupled Receptors: From In vitro Pharmacology to In vivo Mol Pharmacol. 2015; 88:617-23.
