Cytoskeletal regulation of the platelet glycoprotein Ib/V/IX-von willebrand factor interaction.
Shear-induced binding of von Willebrand factor (vWf) to the platelet glycoprotein (GP) Ib/V/IX complex plays a key role in initiating platelet adhesion and aggregation at sites of vascular injury. This study demonstrated that pretreating human platelets with inhibitors of actin polymerization, cytochalasin D or latrunculin B, dramatically enhances platelet aggregation induced by vWf. The effects of these inhibitors were specific to the vWf-GPIbalpha interaction because they enhanced vWf-induced aggregation of Glanzmann thrombasthenic platelets and Chinese hamster ovary (CHO) cells transfected with GPIb/V/IX. Moreover, cytochalasin D enhanced the extent of platelet aggregation induced by high shear stress (5000 s(-1)) and also lowered the shear threshold required to induce aggregation from 3000 s(-1) to as low as 500 s(-1). Studies of CHO cells expressing GPIbalpha cytoplasmic tail truncation mutants that failed to bind actin-binding protein-280 (deletion of residues 569-610 or 535-568) demonstrated that the linkage between GPIb and actin-binding protein-280 was not required for vWf-induced actin polymerization, but was critical for the enhancing effects of cytochalasin D on vWf-induced cell aggregation. Taken together, these studies suggest a fundamentally important role for the cytoskeleton in regulating the adhesive function of GPIb/V/IX.
Mistry
N
N
Department of Medicine, Australian Centre for Blood Diseases, Monash Medical School, Victoria, Australia.
Cranmer
S L
SL
Yuan
Y
Y
Mangin
P
P
Dopheide
S M
SM
Harper
I
I
Giuliano
S
S
Dunstan
D E
DE
Lanza
F
F
Salem
H H
HH
Jackson
S P
SP
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology; D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000648:ultrastructure; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006224:Cricetinae; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism / Q000502:physiology*; D047630:Depsipeptides; D006801:Humans; D016297:Mutagenesis, Site-Directed / Q000502:physiology; D010456:Peptides, Cyclic / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000235:genetics / Q000378:metabolism*; D013314:Stress, Mechanical; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D013915:Thrombasthenia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014162:Transfection; D014841:von Willebrand Factor / Q000187:drug effects / Q000378:metabolism*
D000199:Actins; D000911:Antibodies, Monoclonal; D019086:Bridged Bicyclo Compounds, Heterocyclic; D047630:Depsipeptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D013844:Thiazoles; D053778:Thiazolidines; D014841:von Willebrand Factor; C057531:jasplakinolide; D015638:Cytochalasin D; D000244:Adenosine Diphosphate; D000527:Alprostadil; C037068:latrunculin B