The antithrombotic potential of selective blockade of talin-dependent integrin alpha IIb beta 3 (platelet GPIIb-IIIa) activation.

• In vitro studies indicate that binding of talin to the beta(3) integrin cytoplasmic domain (tail) results in integrin alpha(IIb)beta(3) (GPIIb-IIIa) activation. Here we tested the importance of talin binding for integrin activation in vivo and its biological significance by generating mice harboring point mutations in the beta(3) tail. We introduced a beta(3)(Y747A) substitution that disrupts the binding of talin, filamin, and other cytoplasmic proteins and a beta(3)(L746A) substitution that selectively disrupts interactions only with talin. Platelets from animals homozygous for each mutation showed impaired agonist-induced fibrinogen binding and platelet aggregation, providing proof that inside-out signals that activate alpha(IIb)beta(3) require binding of talin to the beta(3) tail. beta(3)(L746A) mice were resistant to both pulmonary thromboembolism and to ferric chloride-induced thrombosis of the carotid artery. Pathological bleeding, measured by the presence of fecal blood and development of anemia, occurred in 53% of beta(3)(Y747A) and virtually all beta(3)-null animals examined. Remarkably, less than 5% of beta(3)(L746A) animals exhibited this form of bleeding. These results establish that alpha(IIb)beta(3) activation in vivo is dependent on the interaction of talin with the beta(3) integrin cytoplasmic domain. Furthermore, they suggest that modulation of beta(3) integrin-talin interactions may provide an attractive target for antithrombotics and result in a reduced risk of pathological bleeding.

Subject headings

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Keyword

Amino Acid Substitution

Anemia

genetics

metabolism

pathology

Animals

Blood Platelets

metabolism

pathology

Contractile Proteins

genetics

metabolism

Ferric Compounds

toxicity

Fibrinogen

genetics

metabolism

Hemorrhage

genetics

metabolism

pathology

Homozygote

Mice

Mice

Transgenic

Microfilament Proteins

genetics

metabolism

Platelet Glycoprotein GPIIb-IIIa Complex

genetics

metabolism

Point Mutation

Protein Binding

genetics

Protein Structure

Tertiary

genetics

Pulmonary Embolism

chemically induced

genetics

metabolism

pathology

therapy

Talin

genetics

metabolism

Thrombosis

chemically induced

genetics

metabolism

pathology

therapy

Publication and Content Type

ref (subject category)

art (subject category)