Phosphoinositide 3-kinase p110 beta regulates integrin alpha IIb beta 3 avidity and the cellular transmission of contractile forces.
Phosphoinositide (PI) 3-kinase (PI3K) signaling processes play an important role in regulating the adhesive function of integrin alpha(IIb)beta(3), necessary for platelet spreading and sustained platelet aggregation. PI3K inhibitors are effective at reducing platelet aggregation and thrombus formation in vivo and as a consequence are currently being evaluated as novel antithrombotic agents. PI3K regulation of integrin alpha(IIb)beta(3) activation (affinity modulation) primarily occurs downstream of G(i)-coupled and tyrosine kinase-linked receptors linked to the activation of Rap1b, AKT, and phospholipase C. In the present study, we demonstrate an important role for PI3Ks in regulating the avidity (strength of adhesion) of high affinity integrin alpha(IIb)beta(3) bonds, necessary for the cellular transmission of contractile forces. Using knock-out mouse models and isoform-selective PI3K inhibitors, we demonstrate that the Type Ia p110 beta isoform plays a major role in regulating thrombin-stimulated fibrin clot retraction in vitro. Reduced clot retraction induced by PI3K inhibitors was not associated with defects in integrin alpha(IIb)beta(3) activation, actin polymerization, or actomyosin contractility but was associated with a defect in integrin alpha(IIb)beta(3) association with the contractile cytoskeleton. Analysis of integrin alpha(IIb)beta(3) adhesion contacts using total internal reflection fluorescence microscopy revealed an important role for PI3Ks in regulating the stability of high affinity integrin alpha(IIb)beta(3) bonds. These studies demonstrate an important role for PI3K p110 beta in regulating the avidity of high affinity integrin alpha(IIb)beta(3) receptors, necessary for the cellular transmission of contractile forces. These findings may provide new insight into the potential antithrombotic properties of PI3K p110 beta inhibitors.
Schoenwaelder
Simone M
SM
Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, 89 Commercial Road, Melbourne, Victoria 3004, Australia. Simone.Schoenwaelder@med.monash.edu.au
Ono
Akiko
A
Nesbitt
Warwick S
WS
Lim
Joanna
J
Jarman
Kate
K
Jackson
Shaun P
SP
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D058534:Class I Phosphatidylinositol 3-Kinases; D003018:Clot Retraction / Q000187:drug effects / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010973:Platelet Adhesiveness / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D013314:Stress, Mechanical; D013917:Thrombin / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C497132:PIK3CB protein, human; C546640:Pik3cb protein, mouse; D013917:Thrombin