Annexin A2 and the regulation of actin cytoskeletal dynamics

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PI(4,5)P2 enriched membrane microdomains are essentially involved in cell signalling, membrane trafficking, cell motility and polarity. Upon extracellular stimulation, these domains, often called rafts, cluster to form signalling platforms that recruit and accumulate signalling components including those regulating the actin cytoskeleton, thus providing an environment which links cellular signalling and the regulation of actin dynamics. Annexin A2, a substrate of the src-tyrosine kinase and several receptor tyrosine kinases, is one of the best characterized raft-associated proteins. It has recently emerged as a PI(4,5)P2 binding protein and induces the lateral segregation of membrane lipids, suggesting a role in the formation and stabilization of larger raft aggregates. Current evidence indicates a causal role for annexin A2 in the dynamic assembly of actin at rafts, which affects adhesion and motility. We propose that annexin A2 tyrosine phosphorylation functions as a molecular switch that modulates actin-based cellular motility, leading to a more motile phenotype. We want to elucidate the annexin A2 action at a mechanistic level. Firstly, we will characterize the temporal and spatial control of annexin A2 tyrosine phosphorylation. Secondly, we will explore which pathways are targeted by tyrosine phosphorylated annexin A2. Thirdly, we will investigate whether tyrosine phosphorylation of annexin A2 plays a role in tumour biology.We will address these key questions both in vitro and in vivo by biochemical and cell-based approaches, complemented by live cell imaging techniques.