The Effects of Disabled-2 Protein Phosphorylation on Its Interaction with Phospholipid and Platelet Functions

Platelets have critical functions in hemostasis, thrombosis, and immune response. Different types of molecule including transmembrane proteins, protein kinases and adaptor proteins regulate platelet signaling and control its activation. Despite extensive studies, the underlying mechanisms of platelet activation and integrin αIIbβ3 signaling still wait to be fully elucidated. Disabled-2 (Dab2) is a phospho-adaptor protein and is abundantly expressed in human platelets. Its expression regulates integrin αIIbβ3 activation, platelet aggregation, fibrinogen internalization and thrombin signaling. We demonstrated in our recent studies that Dab2 is phosphorylated by PKC at Ser24 and Ser723 when platelets are stimulated by soluble agonists. Dab2 phosphorylation links to either inside-out (for Ser723) or outside-in (for Ser24) signaling of integrin. In particular, Dab2-Ser24 phosphorylation disrupts its interaction with the phospholipid phosphatidic acid, while interference of Dab2-Ser24 phosphorylation inhibits platelet spreading on fibrinogen. However, the functional links between these events and the detailed molecular insights and functions of Dab2-Ser24 phosphorylation in integrin outside-in signaling remains to be elucidated and will be addressed in this grant proposal. In the first year, we will define the molecular basis of Dab2-phosphatidic acid interaction and the impact of Ser24 phosphorylation on the interaction. In the second year, we will investigate the functional impacts of Dab2-phosphatidic acid interaction on platelet signaling and activation and its regulation by Ser24 phosphorylation. In the third year, we will determine the effects of Dab2 and its Ser24 phosphorylation on phosphatidic acid-related platelet functions using in vivo animal model. The accomplishment of this grant proposal should realize the functional roles of Dab2-Ser24 phosphorylation and its effects on Dab2-phospholipid interaction during platelet activation and provide new insight into biomedical sciences, anti-platelet drug development and disease therapy.

Project ID:PC10907-0943
External Project ID:MOST109-2320-B182-031-MY3