Actin assembly in filopodia and lamellipodia: Regulation of the Arp2/3 Complex by Scar and IRSp53

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We aim to determine how actin assembly is regulated in response to activation of various receptors, including during cell spreading. In particular, we want to know how the actin nucleating complex, Arp2/3, is controlled by Scar proteins and by IRSp53 to regulate the balance between filopodia and lamellipodia assembly in platelets and fibroblasts. We have four main aims. Firstly, we have recently discovered that Scar1 null mice have abnormal platelets that do not spread properly on extracellular matrix. Thus, Scar1 appears to be an essential controller of actin dynamics in response to integrin engagement in platelets. We aim to fully characterise the role of Scar1 in platelets. Secondly, we have also found abnormalities in Scar1 null fibroblasts that are distinct from those previously reported by another group. We will determine the role of Scar1 in fibroblast spreading and responses to growth factors using a combination of imaging and biochemical methods. Thirdly, we will also investigate connections between Scars and the exocytic machinery, specifically, the interaction between Scar2 and Sec3. Fourthly, we have solved the crystal structure of a key actin bundling protein and ligand of Scar1, IRSp53 IMD. We will determine how IRSp53 connects to Scar proteins as a mediator of filopod assembly using biophysical and cell biological methods. Our studies are relevant to haemostatic diseases, cancer, inflammation, neurological diseases and wounding. Arp2/3 complex subunits have been implicated in gastric cancers (Kaneda, 2002 #229); Scar proteins may be targets for congenital neurological diseases and cell migration/motility are essential to all of these processes (Kitamura 2003a, 2003b).