Final Report Summary - PROMOTE (The molecular mechanism of the reversible switch between cell proliferation and migration. The regulatory function of the ERK pathway and ERK pathway scaffold RACK1)
Within the Marie Curie international reintegration grant, at the Institute of Microbiology in Prague, we are investigating the mechanism by which ERK signalling can be directed to specific functions by so called 'scaffold' proteins. These non-enzymatic proteins associate with and modulate functional interaction of the components of ERK pathway and couple the components of ERK pathway with upstream activator and downstream targets. The major goal of this project was the understanding the functioning of RACK1, a scaffold protein that associates with core kinases of the ERK pathway: Raf, MEK and ERK and targets active ERK to a specific intracellular location, focal adhesions. Specifically, we investigate the role RACK1 plays in the configuration of the ERK signalling network towards specific biological outcome, cell migration. Our work revealed novel unexpected function of RACK1 as we found that RACK1 induces the disruption of radial symmetry of adhering cells. This process, often referred to as symmetry breaking is crucial for defining cells front and rear and represent prelude to cell migration. The role of ERK and RACK1 in cell motility was further expanded by two closely related areas, the establishment of cell polarity in migrating cells and conversion of epithelial cells to migratory, mesenchymal-like phenotype. Identification of ERK substrates involved in these processes suggested that the specific cellular response is achieved through control of activity of different ERK substrates that are available for phosphorylation by ERK at a given moment in a particular location. Thus, it appears that ERK, through phosphorylation of distinct set of substrates, regulates different cellular subprograms. Consequently, the coordinated execution of these subprograms in time generates complex biological response such as cell migration.