Dissection of a Branched Actin Checkpoint

• Applicant: Dr. Xenia Naj
• Subject Area: Cell Biology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290460928

Cell proliferation is a tightly regulated process, which depends on growth factor stimulation as well as adhesion to the substratum and neighboring cells. Strikingly all these stimuli are associated with actin polymerization and we asked here whether actin polymerization is required to signal proliferation. Our preliminary data indicate that the formation of lamellipodial branched actin networks by the Rac-WAVE-Arp2/3 pathway are monitored in primary cells and immortalized cell lines. These branched actin networks deliver a proliferation signal to the p21WAF1/CIP1 and Rb tumor suppressor genes (TSGs), which are well established machineries regulating the cell cycle. Importantly, requirement for this signalling pathway is systematically lost in transformed cell lines. Our goal is to dissect this signalling pathway that we call the Branched Actin Checkpoint (BAC). To this end, we will first perform a genome wide siRNA screen to identify novel TSGs that relieve the block induced by Arp2/3 inhibition and a proteomics screen to identify the sensor of actin branched junctions in lamellipodia. Then these hits will be ordered in a pathway and their activation mechanism along the BAC pathway will be characterized in terms of protein levels, post-translational modifications and subcellular localizations. Eventually these novel effectors of the BAC will be examined for their involvement in cancer using a retrospective cohort of breast cancer patients. We expect that genetic alterations of new BAC effectors or of their expression levels is associated in a number of cases with poor prognostic for patients. As a consequence, we believe that our work can further refine cancer diagnosis.

• DFG Programme: Research Fellowships
• International Connection: France
• Host: Professor Dr. Alexis Gautreau