The role of the Tec kinase "Bruton´s Tyrosine Kinase" (Btk) in integrin activation and leukocyte 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 leading to leukocyte adhesion to endothelium and transmigration into inflamed tissue. Protein kinases are key regulators of cytoskeletal dynamics and affect many cellular processes, including cell polarity, migration, vesicle trafficking and cytokinesis. The key integrators of signals emanating from G-protein coupled receptors (GPCRs), selectin receptors, and integrin molecules that coordinate these processes are protein tyrosine kinases. Tec-kinases form the second-largest group of non-receptor tyrosine kinases. However, the role of the Tec kinase Brutons tyrosine kinase (Btk) and its upstream and downstream effectors in regulating integrin conformational change and leukocyte recruitment caused by various stimuli remains elusive. Therefore, the aim of this project is to investigate the role of Btk in inside-out signaling (the chemoattractant fMLP and selectin) mediated integrin activation, leukocyte recruitment, and other leukocyte functions by using gene-deficient mice, retrovirus technology, and biochemical methods. Further understanding of the role of Btk in leukocyte recruitment and activation is necessary in order to therapeutically target specific molecules and inhibit specific functions of leukocytes without affecting others.