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Adhesion G protein-coupled receptors (ADGRs) have recently become a target of intense research. Their unique protein structure, which consists of a G protein-coupled receptor combined with long adhesive extracellular domains, suggests a dual role in cell signaling and adhesion. Despite considerable progress in the understanding of ADGR signaling over the past years, the knowledge about ADGR protein networks is still limited. For most receptors, only a few interaction partners are known thus far. We aimed to identify novel ADGR-interacting partners to shed light on cellular protein networks that rely on ADGR function. For this, we applied affinity proteomics, utilizing tandem affinity purifications combined with mass spectrometry. Analysis of the acquired proteomics data provides evidence thatADGRs not only have functional roles at synapses but also at intracellularmembranes, namely at the endoplasmic reticulum, theGolgi apparatus, mitochondria, and mitochondria-associatedmembranes (MAMs). Specifically, we found an association ofADGRswith several scaffold proteins of themembrane-associated guanylate kinases family, elementary units of the γ-secretase complex, the outer/innermitochondrial membrane,MAMs, and regulators of the Wnt signaling pathways. Furthermore, the nuclear localization of ADGR domains together with their physical interaction with nuclear proteins and several transcription factors suggests a role of ADGRs in gene regulation. [ABSTRACT FROM AUTHOR]