Molecular and functional characterization of the unconventional interaction partners of CXCR7 and their role in virus-associated tumorigenesis

CXCR7 is an atypical and enigmatic chemokine receptor playing crucial roles in numerous physiological processes but also in viral infection and cancer. To date, the exact functions and signaling properties of CXCR7 are still a matter of debate. Unlike other chemokine receptors, CXCR7 is proposed to act as a scavenging receptor for its ligands, to trigger arrestin-dependent signaling and possibly classical G-protein mediated signaling. Besides its two endogenous chemokines CXCL11 and CXCL12 and the virus-encoded chemokine vCCL2, accumulating evidence suggest that CXCR7 interacts with several non-chemokine ligands such as the pro-angiogenic peptide Adrenomedullin (ADM). Furthermore, calcitonin receptor like receptor (CLR) and receptor activity modifying proteins (RAMPs), constituting the main ADM receptor, might crosstalk with CXCR7 conferring the receptor alternative functions. While the interactions of CXCR7 with classical chemokine ligands are now well characterized, little is known about the interdependence of ADM and the membrane interacting partners with CXCR7, the signaling pathways activated as well as their roles in viral infection and tumorigenesis.
The aims of this PhD project are to 1) unravel the role and impact of CLR and RAMPs on the binding, scavenging and signaling properties of CXCR7 towards the different ligands ADM, CXCL12, CXCL11 and vCCL2. Additionally, by using state-of-the-art techniques like Bioluminescence Resonance Energy Transfer (BRET), we will 2) inquire the ability of CXCR7 to heterodimerize with CLR and RAMPs. Lastly, since CXCR7 and RAMPs were described to be upregulated upon infection by several tumorigenic viruses, 3) a detailed expression profile of all the ligands and partners of CXCR7 in a herpesvirus-induced cancer model will be determined and will help to reveal the role of CXCR7 in viral associated tumorigenesis. This project will allow improving our level of understanding of CXCR7 regulation and functions and will open new therapeutic directions for selective CXCR7 inhibition.