GPCR-mediated oncogenic signaling, targeting 14-3-3 as mediators of apoptotic/proliferative switching
Summary of the proposed research
G-protein coupled receptors (GPCRs) are implicated in a large number of pathologies, ranging from allergic responses, inflammatory diseases to cancer. Aberrant GPCR signalling has been shown to induce transformation and contribute to the onset or progression of oncogenesis (1-2). Notably, the family of chemokine receptors, known to be involved in the control and regulation of the immune system, also plays a key role in cancer and more specifically tumor metastasis (3). Chemokine receptors, like CXCR4 and CXCR7 and their ligand CXCL12, are induced in various types of tumor cells and are responsible for tumor metastasis (4-5). Interestingly, several herpes- and capripoxviridae encode chemokine receptor homologues that are hypothesized (ORF74, Kaposi Sarcoma Virus, KSHV) or oncomodulary processes (US28; Human Cytomegalovirus, HCMV) (6-7).
In our study on US28-mediated signalling we find a prominent role for members of the 14-3-3 protein family: i) several proteins involved in US28-triggered responses are 14-3-3 targets, ii) in a proteomic approach aimed at the characterization of the US28 signalling complex, several 14-3-3 isoforms co-immunoprecipitated with the vGPCR
The 14-3-3 protein family has taken the status of a central regulator in cell biology since it is involved in key cellular processes (9). They interact with a wide range of target proteins in a phosphorylation-dependent mannerand are core players in phospho-regulatory pathways controlling signal transduction, cell-cycle regulation and apoptosis (10-11). Cell fate is a delicate balance between anti-apoptotic (pro-survival) and apoptotic signalling and 14-3-3 interacts with multiple proteins from both pathways. In this study we will identify and investigate the role of 14-3-3 proteins and their target proteins in GPCR- mediated (oncogenic-) signalling and modulate specific cellular responses using the 14-3-3 modulating fusicoccanes Fusicoccin (FC) and Cotylenin A (Cot-A).
