| First Author | Chen X | Year | 2013 |
| Journal | Blood | Volume | 121 |
| Issue | 18 | Pages | 3718-26 |
| PubMed ID | 23444402 | Mgi Jnum | J:197452 |
| Mgi Id | MGI:5493150 | Doi | 10.1182/blood-2012-10-461897 |
| Citation | Chen X, et al. (2013) PDK1 regulates platelet activation and arterial thrombosis. Blood 121(18):3718-26 |
| abstractText | The effects of phosphoinositide-dependent protein kinase 1 (PDK1), a master kinase in the phosphoinositide 3-kinase/Akt pathway, on platelet activation are unknown. Accordingly, platelet-specific PDK1-deficient mice were characterized to elucidate the platelet-related function(s) of PDK1. We found that PDK1 deficiency caused mild thrombocytopenia. The aggregation of PDK1(-/-) platelets was diminished in response to low levels of thrombin, U46619, and adenosine 5'-diphosphate. Further results demonstrated that PDK1 regulates thrombin-induced platelet activation by affecting alphaIIbbeta3-mediated outside-in signaling. This result provided an explanation for the diminished spreading of PDK1(-/-) platelets on immobilized fibrinogen (Fg) and the decreased rate of clot retraction in platelet-rich plasma (PRP) containing PDK1(-/-) platelets. PDK1 deficiency diminished agonist-induced Akt Ser473 phosphorylation and thoroughly abolished Akt Thr308 and Gsk3beta Ser9 phosphorylation in response to agonist treatment and platelet spreading, respectively. A Gsk3beta inhibitor fully restored the aggregation of PDK1(-/-) platelets in response to low levels of thrombin, normal spreading of PDK1(-/-) platelets on Fg, and normal clot retraction in PRP containing PDK1(-/-) platelets. Those results indicated that Gsk3beta is one of the major downstream effectors of PDK1 in thrombin-induced platelet activation and alphaIIbbeta3-mediated outside-in signaling. In addition, in vivo data demonstrated that PDK1 is an important regulator in arterial thrombosis formation. |
