A11 - Gohla

Summary

The morphological and functional changes of activated platelets that ultimately trigger platelet aggregation are mediated by a profound reorganization of the actin cytoskeleton. The final stages of platelet activation involve an engagement of the fibrinogen receptor αIIbβ3 integrin, which therefore represents an important target for pharmacological inter-ventions. Despite their importance for hemostasis and thrombosis, the molecular mechanism underlying the αIIbβ3 mediated actin cytoskeletal remodeling are still insufficiently understood.

Proteins of the cofilin family and Src family kinases are key regulators of αIIbβ3 mediated actin dynamics in platelets. We have identified an activation mechanism of the cofilin phosphatase Chronophin that points to a role of Chronophin for αIIbβ3 dependent functions in platelets. While the role of Src family kinases for αIIbβ3 functions is well established, the molecular determinants and the dynamics of Src phosphoregulation in platelets remain poorly understood. We have discovered AUM, a novel Src regulatory tyrosine phosphatase that functions in adhesion by an as yet unknown activation mechanism.

We employ biochemical and cell biological methods to analyze the functions of Chronophin and AUM for αIIbβ3 mediated actin cytoskeletal reorganization in platelets. Using newly established mouse models, we investigate the roles of these phosphatases for hemostasis and thrombosis. The aim of our study is the gain fundamental insights into the regulation of αIIbβ3 mediated actin dynamics, and to contribute to a detailed understanding of the molecular basis of platelet cell interactions and thromboembolic processes.