Regulation of Rho family GTPases by DOCK GEFsThe Rho proteins are Ras-like small GTPases acting as central players in shaping the cell actin skeleton. A major ongoing project in the lab is centered on the study of the DOCK180/ELMO complex and it role in promoting Rac-mediated cytoskeleton reorganization. This signalling pathway is evolutionarily conserved and the DOCK180 orthologues in the nematode C. elegans (Ced-5) and in Drosophila (Myoblast City) are involved in cell migration, axon guidance and myoblast fusion. We recently demonstrated the domains involved in Rac activation (DHR-2) and membrane targeting (the PIP3 binding module named DHR-1). Furthermore, we demonstrated the multifaceted mechanism of interaction between DOCK180 and ELMO proteins. This work establishes the foundation for further investigations on the exact roles of ELMO proteins in Rac signalling. Dr Côté’s group relies on biochemical, cellular, genetic and structural approaches in order to understand the role of the DOCK180/ELMO-Rac pathway(s) in cell migration.
Biological Processes Regulated by DOCK GEFs.The biological functions of DOCK GEFs in mammals are poorly understood. We recently demonstrated that DOCK180 and DOCK5 are critical regulators of myoblast fusion using mouse mutant models. This phenotype is highly reminiscent of the myoblast fusion defects observed in flies with inactivated Myoblast City. We are now investigating the molecular players involved in myoblast fusion with the aim of identifying the biological mechanisms regulated by the DOCK180/Rac pathway. In addition, we are exploring the role of the DOCK180/DOCK5 GEFs in signalling initiated by myoblast fusion receptors, including Nephrin, during kidney development. In the long term, these studies will also provide important insight in molecular pathways implicated in diseases such as muscular dystrophies and nephrotic syndromes.
Receptor Tyrosine Kinases-Mediated Signalling pathways Driving Cell Invasion and MetastasisReceptor Tyrosine Kinases (RTKs) are key cell surface molecule driving proliferation and survival and are also important signal transducers that promote cell invasion and metastasis in cancer. We are currently focusing on “metastatic” signalling pathways downstream of the HER-2 and Axl RTKs as this is the deadliest step of cancer progression. These two kinases are activated in a large number of human breast cancers where they promote tumour growth and dissemination to other sites of the body. Using transgenic mouse models, cell based assays, proteomic approaches and cell signalling technologies, we hope to define novel pathways that will be relevant for therapeutic targeting with the goal of preventing breast cancer spreading in patients.