In vivo Functional Analysis of Platelet Protein Disabled-2 in Hemostasis and Platelet Aggregation

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Disabled-2 (DAB2) is an adapter protein that is implicated in growth factor signaling, endocytosis, cellular adhesive function, and hematopoietic cell differentiation. Recent study in our laboratory unveils that DAB2 is expressed abundantly in platelets. DAB2 is distributed in the platelet 脈-granules and is released from the granular compartment upon platelet activation. The secreted DAB2 binds to the extracellular region of integrin 脈IIb芻3 on the platelet surface through the phosphotyrosine binding domain. The DAB2-platelet interactions result in the inhibition of agonist-induced platelet aggregation. Biochemical and mutational analysis revealed that the DAB2 RGD motif (aa. 64-66) and the integrin 脈IIb fibrinogen binding region (aa. 171-464) are important for the DAB2-platelet interactions. Such interactions compete for the binding of 脈IIb with fibrinogen and provide a mechanism for DAB2 to inhibit platelet aggregation. These findings demonstrate for the first time that DAB2 is an integrin 脈IIb-binding protein that plays a novel role in the control of platelet-fibrinogen interactions and platelet aggregation. Based on these observations, we hypothesize that DAB2 elicits in vivo anti-platelet activity of which the cellular signaling needed to be investigated further. At the first and second year, DAB2 transgenic and conditional knockout mice model will be established. The effect of DAB2 on agonist-induced platelet signaling will also be analyzed. At the second and third year, in vivo and in vitro platelet functions will be characterized using the mice model we generated. In the mean time, the interaction of DAB2 with platelet proteins will also be investigated. Together, the accomplishment of this grant proposal will clarify the in vivo role of DAB2 in platelet function and platelet signaling.

Project IDs

Project ID:PC9708-0325
External Project ID:NSC95-2320-B182-023-MY3
StatusFinished
Effective start/end date01/08/0731/07/08

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.