EPAC1 regulates endothelial Annexin A2 cell surface translocation and plasminogen activation

Abstract

Annexins, a family of highly conserved calcium-and phospholipid-binding proteins, play important roles in a wide range of physiological functions. Among the twelve known annexins in human, Annexin A2 (AnxA2) is one of the most extensively studied and has been implicated in various human diseases. AnxA2 can exist as a monomer or a heterotetrameric complex with S100A10 (P11) and plays a critical role in many cellular processes including exocytosis/endocytosis and membrane organization. At the endothelial cell surface, (AnxA2•P11)2 tetramer, acting as a coreceptor for plasminogen and tissue plasminogen activator (t-PA), accelerates t-PA dependent activation of the fibrinolytic protease, plasmin, the enzyme responsible for thrombus dissolution and degradation of fibrin. This study shows that exchange proteins directly activated by cAMP isoform 1 (EPAC1) interacts with AnxA2 and regulates its biological functions by modulating its membrane translocation in endothelial cells. Using genetic and pharmacological approaches, it is demonstrated that EPAC1, acting through the PLCε-PKC pathway, inhibits AnxA2 surface translocation and plasminogen activation. These results suggest that EPAC1 plays a role in the regulation of fibrinolysis in endothelial cells and may represent a novel therapeutic target for disorders of fibrinolysis.

Tuning the endothelial response: differential release of exocytic cargos from Weibel‐Palade bodies

“…7). Because PKCa can be activated directly by both DAG and calcium [50] or indirectly via cAMP-dependent agonists and EPAC (exchange proteins directly activated by cAMP isoform) [51,52], PKC activation could feasibly occur downstream of any of the ring-recruiting agonists that we, and others, have identified. The cAMP-raising secretagogues forskolin and adrenalin have previously been identified by others [25] as stimulating actin ring recruitment.…”