Molecular characterization of Skap2 for integrin activation and leukocyte activation and recruitment

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Leukocyte recruitment into inflamed tissue proceeds in a cascade-like fashion. The first contact of neutrophils with the endothelium is mediated by selectins and their counter-receptors, followed by rolling and integrin-mediated arrest. While rolling, neutrophils collect different inflammatory signals which can activate several pathways. In addition to activation of neutrophils by G-protein coupled receptor (GPCR) engagement, integrins and selectin ligands are also able to signal into the cell. These signaling pathways may fully activate neutrophils, but they are poorly understood. I propose to investigate whether Skap2 is involved in integrin activation, leukocyte recruitment, and other neutrophil functions. The role of Skap2 in inside-out- (selectin- and GPCR-triggered) and outside-in integrin signaling will be investigated by using gene-deficient mice, retrovirus technology, in vitro assays, and biochemical methods. Additionally, we will explore and investigate downstream effectors of Skap2 and subsequently do structure-function analysis in vitro and in vivo to investigate the physiological relevance. The further understanding of these signaling pathways is necessary in order to therapeutically target specific molecules and inhibit specific functions of neutrophils without affecting others.