Deletion of the p110beta isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo.
During platelet activation, phosphoinositide 3-kinases (PI3Ks) produce lipid second messengers participating in the regulation of functional responses. Here, we generated a megakaryocyte-restricted p110beta null mouse model and demonstrated a critical role of PI3Kbeta in platelet activation via an immunoreceptor tyrosine-based activation motif, the glyco-protein VI-Fc receptor gamma-chain complex, and its contribution in response to G-protein-coupled receptors. Interestingly, the production of phosphatidylinositol 3,4,5-trisphosphate and the activation of protein kinase B/Akt were strongly inhibited in p110beta null platelets stimulated either via immunoreceptor tyrosine-based activation motif or G-protein-coupled receptors. Functional studies showed an important delay in fibrin clot retraction and an almost complete inability of these platelets to adhere onto fibrinogen under flow condition, suggesting that PI3Kbeta is also acting downstream of alpha(IIb)beta(3). In vivo studies showed that these mice have a normal bleeding time and are not protected from acute pulmonary thromboembolism but are resistant to thrombosis after FeCl(3) injury of the carotid, suggesting that PI3Kbeta is a potential target for antithrombotic drugs.
Martin
Valérie
V
Inserm, U563, Centre de Physiopathologie de Toulouse Purpan, Département d'Oncogenèse, Signalisation et Innovation thérapeutique, and Université Toulouse III Paul-Sabatier, Toulouse, France.
Guillermet-Guibert
Julie
J
Chicanne
Gaétan
G
Cabou
Cendrine
C
Jandrot-Perrus
Martine
M
Plantavid
Monique
M
Vanhaesebroeck
Bart
B
Payrastre
Bernard
B
Gratacap
Marie-Pierre
MP
D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D002712:Chlorides; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D005290:Ferric Compounds; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D007527:Isoenzymes / Q000235:genetics; D008533:Megakaryocytes / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010974:Platelet Aggregation / Q000235:genetics; D013927:Thrombosis / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
D002712:Chlorides; D005290:Ferric Compounds; D007527:Isoenzymes; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; C024555:ferric chloride