Disabled-2 is a novel alphaIIb-integrin-binding protein that negatively regulates platelet-fibrinogen interactions and platelet aggregation.
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.
Huang
Chien-Ling
CL
Graduate Institute of Basic Medical Sciences, Chang Gung University, Taoyuan 333, Taiwan, Republic of China.
Cheng
Ju-Chien
JC
Stern
Arnold
A
Hsieh
Jer-Tsong
JT
Liao
Chang-Hui
CH
Tseng
Ching-Ping
CP
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins; D001792:Blood Platelets / Q000378:metabolism*; D002448:Cell Adhesion; D002454:Cell Differentiation; D005340:Fibrinogen / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D020014:K562 Cells; D008533:Megakaryocytes / Q000166:cytology; D009842:Oligopeptides / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D013917:Thrombin / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D009842:Oligopeptides; D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D025521:Tumor Suppressor Proteins; C047981:arginyl-glycyl-aspartic acid; D005340:Fibrinogen; D013917:Thrombin