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
External Project ID:NSC95-2320-B182-023-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/07 → 31/07/08 |
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