The role of endothelial cortactin in vascular permeability and leukocyte extravasation

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Leukocyte extravasation is a central component of the inflammatory response and occurs in a series of molecular events including adhesion, signaling and cytoskeletal remodeling. If not controlled properly, excessive extravasation can lead to chronic inflammatory diseases. We have shown that endothelial cortactin regulates vascular permeability and neutrophil extravasation at sites of inflammation in vivo. In functional studies, we demonstrated that cortactin controls the activity of small GTPases: Rap1 is less active in cortactin-deficient cells, whereas RhoG cannot be activated upon leukocyte binding to endothelial cells. My preliminary data suggest that the vasoactive peptide adrenomedullin (ADM) and the Rap1 activator PDZ-GEF2 support cortactin-mediated regulation of endothelial functionality. Moreover, we found that the major endothelial receptor for leukocytes, ICAM-1, cannot cluster around leukocytes without cortactin. In this project, I want to unravel the molecular mechanisms by which cortactin regulates leukocyte extravasation and vascular permeability. I will analyze if cortactin acts as scaffold to coordinate the molecular machinery required for controlled GTPase activation. Additionally, I will examine how cortactin regulates ICAM-1 clustering to control leukocyte extravasation. This can occur through connecting ICAM-1 to the actin cytoskeleton and/or via disturbed signal transduction downstream of leukocyte capture. I will also search for new binding partners of cortactin under inflammatory conditions and for proteins that are differentially regulated in the absence of cortactin. The results of these studies will clarify the mechanisms of cortactin-mediated signaling during the immune response and may identify cortactin as target in novel treatment strategies for chronic inflammatory disorders.