Spatio-temporal control of Rac1 by its atypical regulator Bcr at the membrane periphery – BiRaC

Cells established a spectacular protein network that enables them to receive and process signals. Among the essential proteins orchestrating signaling, the family of small GTPases plays a central role by functioning as molecular switches that alternate between an inactive form bound to GDP and an active form bound to GTP which transmits signals. The activation-inactivation cycle of GTPases must be tightly controlled to ensure appropriate molecular action and specificity of response. In this project, we are interested in Rac1, a regulator of cell motility, endocytosis and growth. Rac1 is regulated by GEFs and GAPs, which allow a rapid and localized response to perturbation to ensure efficient polymerization of actin during cell migration or adhesion. In addition to its classic regulators, Rac1 also has an atypical regulator, Bcr (Breakpoint Cluster Region protein) which carries both GEF and GAP activities. The function of Bcr is not known, it has been mainly studied in the context of the Philadelphia chromosome, the genetic anomaly where the Bcr-Abl chimera, produced by chromosomal rearrangement and truncation of Bcr, is implicated in leukemia caused by an excessive activity of Abl1 kinase. Surprisingly, how the truncation in Bcr affects its regulation of Rac1 has never been studied. In addition, little is known about the regulation of Rac1 by the atypical GEF / GAP activities of wild-type Bcr. My aim is to determine how the GEF and GAP activities of the atypical regulator Bcr control Rac1 activity at the periphery of membrane in a quantitative manner, how this activity is supported by the Bcr structure and the conformational changes upon binding to the membrane and discover defects in Rac1 regulation in the oncogenic Bcr-Abl fusion.