New dimensions in CXCR4 and Rac1 regulation

To gain more insights in the molecular mechanisms regulating cellular migration, which is an important process involved in beneficial biological processes as well as in pathological conditions, we focused our research on two crucial proteins, i,e. the chemokine receptor CXCR4 and the small GTPase Rac1. We have investigated the interplay between these two proteins as well as their individual regulation and function. Our research was particularly focused on the role for Rac1 in regulating the responsive conformation of the CXCR4 receptor. This work established a previously unrecognized role for Rac1 in fine-tuning CXCR4 responses. We identified a region in CXCR4 that mediates Rac1 signaling and subsequently regulates the receptor’s conformation. In addition, we identified the CXCR4-binding protein nucleophosmin1 (NPM1) as a novel negative regulator of Rac1 activity and found that, reciprocally, Rac1 regulates NPM1 subcellular localization. Finally, we address the importance of the hypervariable C-terminus of Rac1 in regulating its function.