Evaluation of CD97 signaling
Gabriela Aust, Leipzig University
The signaling of of the prototypic aGPCR CD97 likely depends on the regulated subcellular residence of the receptor, which locates within lateral cell contacts of normal intestinal epithelial cells but intracellularly and at the leading edge of the corresponding (migrating) tumor cells. This indicates context-dependent CD97 functions, which are based on specific molecular signal pathways and interaction partners. Project P8 will address the following points:
1) The N-terminal extracellular stretch of CTF (= stachel peptide) probably acts as a tethered agonist in aGPCR signaling. We will clarify whether CD97 could be specifically activated by the stachel peptide.
2) Identification of the intracellular interaction partners of CD97 will help to link it to signaling cascades and molecular networks depending on the cellular context. Tandem affinity purification (TAP) will be conducted to address how the CD97 interactome looks like. The role of phosphorylation for the context-dependent change in CD97 function will be verified. Interaction partners of the PDZ-domain binding motif at the extreme C-terminus of CD97 will be identified using a PDZ-array.
The long-term aim of this project is to evaluate and verify signaling models for the CD97 NTF, CTF and NTF-CTF interplay and to characterize the intracellular interaction and signaling partners of CD97. This will allow new insights into common and CD97-specific functions and signaling routes of this receptor.
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.
Hilbig D, Dietrich N, Wandel E, Gonsior S, Sittig D, Hamann J, Aust G (2018) The Interaction of CD97/ADGRE5 With β-Catenin in Adherens Junctions Is Lost During Colorectal Carcinogenesis. Front Oncol. 8: 182.
Aust G, Zhu D, Van Meir EG, Xu L (2016) Adhesion GPCRs in Tumorigenesis. Handbook of Experimental Pharmacology 234:369-396.
Hamann J, Aust G, Arac D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin H-H, 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, and Schiöth HB (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein-Coupled Receptors. Pharmacological Reviews 67:338–367.
Liebscher I, Ackley B, Araç D, Ariestanti DM, Aust G, Bae BI, Bista BR, Bridges JP, Duman JG, Engel FB, Giera S, Goffinet AM, Hall RA, Hamann J, Hartmann N, Lin HH, Liu M, Luo R, Mogha A, Monk KR, Peeters MC, Prömel S, Ressl S, Schiöth HB, Sigoillot SM, Song H, Talbot WS, Tall GG, White JP, Wolfrum U, Xu L, Piao X. New functions and signaling mechanisms for the class of adhesion G protein-coupled receptors. Ann N Y Acad Sci. 2014; 1333:43-64.
Araç D, Aust G, Calebiro D, Engel FB, Formstone C, Goffinet A, Hamann J, Kittel RJ, Liebscher I, Lin HH, Monk KR, Petrenko A, Piao X, Prömel S, Schiöth HB, Schwartz TW, Stacey M, Ushkaryov YA, Wobus M, Wolfrum U, Xu L, Langenhan T. Dissecting signaling and functions of adhesion G protein-coupled receptors. Ann N Y Acad Sci. 2012; 1276(1):1-25.