A shear-restricted pathway of platelet procoagulant activity is regulated by IQGAP1.
Circulating blood platelets regulate the initial phase of the hemostatic response through adhesive and aggregatory events and by providing the necessary procoagulant surface for prothrombinase complex assembly and thrombin generation. The signaling pathway(s) that regulate platelet procoagulant activity are largely unknown, although they are distinct from platelet aggregatory signals linked to fibrinogen ligation to the conformationally active alpha(IIB)beta(3) integrin. We describe a novel intracellular signaling mechanism involving platelet IQGAP1 that specifically regulates the development of platelet procoagulant activity under conditions of mechanical shear stress. Murine platelets that are deficient in IQGAP1 demonstrate increased prothrombinase activity compared with wild-type littermate controls when activated by a physiological shear stress of 16 dynes/cm(2) (shear rates of 1600 s(-1)) (p < 0.0001), corresponding to approximately 2.5 times the normal shear stress, or approximately 40% degree of stenosis in coronary arteries. The exaggerated prothrombinase activity is not associated with enhanced platelet microvesiculation (cytoskeletal proteolysis) and occurs independently of the intracellular calcium release, [Ca(2+)](i), but it is specifically coupled to the alpha-granule exocytic pathway without concomitant effects on aminophospholipid exposure. These observations identify platelet IQGAP1 as an important modulator of normal hemostasis and as an appropriate pharmacological target for control of platelet procoagulant function.
Bahou
Wadie F
WF
Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York 11794-8151, USA. wbahou@ notes.cc.sunysb.edu
Scudder
Lesley
L
Rubenstein
David
D
Jesty
Jolyon
J
D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry* / Q000502:physiology; D002448:Cell Adhesion; D002850:Chromatography, Gel; D003029:Coagulants / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins; D006487:Hemostasis; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry; D011487:Protein Conformation; D015398:Signal Transduction; D013314:Stress, Mechanical; D013917:Thrombin / Q000737:chemistry; D013925:Thromboplastin / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D020703:ras GTPase-Activating Proteins
D002352:Carrier Proteins; D003029:Coagulants; C101203:IQ motif containing GTPase activating protein 1; D008164:Luminescent Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D020703:ras GTPase-Activating Proteins; D049452:Green Fluorescent Proteins; D013925:Thromboplastin; D013917:Thrombin; D002118:Calcium