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J Cell Sci. 2006 Nov 1;119(Pt 21):4420-30.

Disabled-2 is a novel alphaIIb-integrin-binding protein that negatively regulates platelet-fibrinogen interactions and platelet aggregation.

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  • 1Graduate Institute of Basic Medical Sciences, Chang Gung University, Taoyuan 333, Taiwan, Republic of China.

Abstract

Platelet aggregation plays a pivotal role in the haemostatic process and is involved in the pathological counterpart of arterial thrombosis. We have shown that the adapter protein disabled-2 (DAB2) is expressed abundantly in platelets. In this study, DAB2 was found to distribute in the platelet alpha-granules and was released from the granular compartment upon platelet activation. The secreted DAB2 binds to the extracellular region of alphaIIbbeta3 integrin on the platelet surface through the phosphotyrosine-binding domain. The DAB2-platelet interactions result in the inhibition of agonist-induced platelet aggregation with the exception of thrombin, a DAB2 protease that renders DAB2 inactive. Biochemical and mutational analysis revealed that the DAB2 cell-adhesion Arg-Gly-Asp (RGD) motif (amino acid residues 64-66) and the alphaIIb-integrin-fibrinogen-binding region (amino acid residues 171-464) are important for the DAB2-platelet interactions. Such interactions compete for the binding of alphaIIb integrin with fibrinogen and provide a mechanism for DAB2 to inhibit platelet aggregation. Accordingly, the synthetic RGD-motif-containing DAB2 peptide PDARGDKM also elicited anti-platelet aggregation activity. These findings demonstrate for the first time that DAB2 is an alphaIIb-integrin-binding protein that plays a novel role in the control of platelet-fibrinogen interactions and platelet aggregation.

PMID:
17074833
[PubMed - indexed for MEDLINE]
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