Abstract：
:3-phosphoinositide-dependent protein kinase 1 (PDK1), a member of the protein A,G and C (AGC) family of proteins, is a Ser/Thr protein kinase that can phosphorylate and activate other protein kinases from the AGC family, including Akt at Thr308, all of which play important roles in mediating cellular responses. The functional role of PDK1 or the importance of phosphorylation of Akt on Thr308 for its activity has not been investigated in human platelets. In this study, we tested two pharmacological inhibitors of PDK1, BX795 and BX912, to assess the role of Thr308 phosphorylation on Akt. PAR4-induced phosphorylation of Akt on Thr308 was inhibited by BX795 without affecting phosphorylation of Akt on Ser473. The lack of Thr308 phosphorylation on Akt also led to the inhibition of PAR4-induced phosphorylation of two downstream substrates of Akt, viz. GSK3β and PRAS40. In vitro kinase activity of Akt was completely abolished if Thr308 on Akt was not phosphorylated. BX795 caused inhibition of 2-MeSADP-induced or collagen-induced aggregation, ATP secretion and thromboxane generation. Primary aggregation induced by 2-MeSADP was also inhibited in the presence of BX795. PDK1 inhibition also resulted in reduced clot retraction indicating its role in outside-in signalling. These results demonstrate that PDK1 selectively phosphorylates Thr308 on Akt thereby regulating its activity and plays a positive regulatory role in platelet physiological responses.
journal_name
Thromb Haemostjournal_title
Thrombosis and haemostasisauthors
Dangelmaier C,Manne BK,Liverani E,Jin J,Bray P,Kunapuli SPdoi
10.1160/TH13-06-0484subject
Has Abstractpub_date
2014-03-03 00:00:00pages
508-17issue
3eissn
0340-6245issn
2567-689Xpii
13-06-0484journal_volume
111pub_type
杂志文章abstract：:We tested the response of the fibrinolytic activity and factor VIII-antigen levels to infusion of DDAVP in healthy volunteers and we studied the influence of propranolol and aspirin on this response. After DDAVP, 0.4 microgram/kg in 10 min i.v., the fibrinolytic activity of redissolved euglobulins rose from 179 to 452...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1984-02-28 00:00:00
abstract：:Some classical hemophiliacs have a paradoxical hemostatic response to prothrombin complex concentrate (PCC). We hypothesized that vascular endothelial cells (EC) may contribute to this "factor VIII bypassing activity". When PCC were incubated with suspensions or monolayer cultures of EC, they acquired the ability to p...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1988-10-31 00:00:00
abstract：:The turnover of recombinant pro-urokinase (Rec-pro-UK), recombinant urokinase (Rec-UK) and natural urinary urokinase (Nat-UK) was studied in rabbits and in squirrel monkeys (Saimiri sciureus). Following intravenous injection, urokinase activity disappeared rapidly from the blood. The initial disappearance rate could b...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1984-08-31 00:00:00
abstract：:When compared to normal megakaryocytes, those from a patient with the giant platelet syndrome exhibited numerous cytochemical abnormalities. These reflected disturbances in the metabolism of RNA, glycogen, arginine-rich histone, and various glycolytic enzymes. Ultrastructural studies of the abnormal megakaryocytes als...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1977-10-31 00:00:00
abstract：:Heparin is often used as an adjunct to thrombolytic therapy in order to prevent reocclusion of the patent vessels in patients with thrombotic disease. Controversy exists as to whether heparin is required for effective clot lysis with tissue-type plasminogen activator, while in vitro data and small scale clinical trial...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1993-04-01 00:00:00
abstract：: ...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1055/s-0038-1657075
更新日期：1979-07-01 00:00:00
abstract：:Adhesion of rat blood platelets to native rat tail collagen fibrils was studied in the electron microscope under conditions that preserved collagen-associated proteoglycans (CAPG). The CAPG molecules were aligned in chain-like configurations that encircled the fibrils with a 65 nm period; they appeared to coat the fib...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1987-08-04 00:00:00
abstract：:Heparin-induced thrombocytopenia (HIT), a relatively common complication of heparin therapy, results of platelet activation, via the receptor for the Fc domain of IgG (FcgammaRIIa), by heparin-dependent-antibodies, commonly directed against the heparin-platelet factor 4 (H-PF4) antigenic complex. Our strategy was to u...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2001-06-01 00:00:00
abstract：:In this study, we investigate the influence of three factor VII (FVII) gene polymorphisms on activated FVII levels (FVIIa), and also on the risk of myocardial infarction (MI) in patients with advanced coronary atherosclerotic disease (CAD). The -323A2 allele in the promoter is known to be associated with low FVII leve...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH04-02-0130
更新日期：2004-09-01 00:00:00
abstract：:The alphaII(b)beta3 integrin and FcgammaRII receptors mediate, respectively, platelet adhesion and spreading on fibrinogen and immunoglobulin (IgG) coated surfaces. Platelet adhesion to fibrinogen resulted in a partial conversion of the faster to the slower migrating (phosphorylated) form of Ca(+2)-sensitive cytosolic...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1999-04-01 00:00:00
abstract：:Seasonal variation in venous thromboembolism (VTE) risk in individuals with familial predisposition to VTE has not been explored. This nationwide study aimed to determine whether there are age- and sex-specific seasonal differences in risk of hospitalisation of VTE among individuals with and without a family history o...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH13-04-0320
更新日期：2013-12-01 00:00:00
abstract：:Hypercoagulability may increase the risk of cardiovascular disease (CVD) in diabetic patients with albuminuria. Plasma thrombin-anti-thrombin III complex (TAT) levels, representing a functional state of clotting system, were studied in one hundred and fifteen non-insulin-dependent diabetic (NIDDM) patients. The patien...
journal_title：Thrombosis and haemostasis
pub_type： 临床试验,杂志文章,随机对照试验
doi：
更新日期：1995-11-01 00:00:00
abstract：:Fibrinogen Matsumoto V (M-V) is a dysfibrinogen identified in a 52-year-old woman with systemic lupus erythematous. The triplet AGG encoding the amino acid residue Aalpha19 was replaced by GGG, resulting in the substitution of Arg-->Gly. Residue Aalpha19 has been shown to be one of the most important amino acids in th...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2001-01-01 00:00:00
abstract：:We have investigated the effect of a new Leu196Pro mutation, identified in the MIDAS-like domain of the beta3 integrin subunit in a patient with type II Glanzmann thrombasthenia, on beta3 integrin receptor function. Expression of the mutant beta3Pro196 subunit in CHO cells, either associated with recombinant human alp...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2001-12-01 00:00:00
abstract：:Von Willebrand factor (vWF) is synthesized by human endothelial cells and megakaryocytes as a large precursor, the pre-provWF, which is finally cleaved into the propolypeptide of vWF (pp-vWF) and the mature vWF. We have purified in parallel the pp-vWF and the GP IIb-IIIa from porcine platelets. The N-terminus comparat...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1998-10-01 00:00:00
abstract：:Compelling evidence suggests that the risk of pulmonary embolism (PE) and deep-vein thrombosis (DVT) persists after hospital discharge in acutely-ill medical patients. However, no studies consistently supported the routine use of extended-duration thromboprophylaxis (ET) in this setting. We performed a meta-analysis t...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,meta分析
doi：10.1160/TH16-08-0595
更新日期：2017-02-28 00:00:00
abstract：:The increased risk for deep vein thrombosis (DVT) after orthopaedic surgery has been well documented as well as hypercoagulable state during both total hip arthroplasty (THA) and total knee replacement (TKR). To investigate the influence of the surgical procedure [posterolateral (PL) or lateral (L) approach for THA, u...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1999-06-01 00:00:00
abstract：:We report for the first time that saliva of the hard tick and Lyme disease vector, Ixodes scapularis, is a potent inhibitor of angiogenesis. Saliva (< or = 1:500 dilutions) or salivary gland (0.1-0.5 pairs/assay) dose-dependently inhibits microvascular endothelial cell (MVEC) proliferation. Inhibition was also detecte...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：10.1160/TH04-09-0566
更新日期：2005-07-01 00:00:00
abstract：:The first step of coagulation factor XIII (FXIII) activation involves cleavage of the FXIII activation peptide (FXIII-AP) by thrombin. However, it is not known whether the FXIII-AP is released into plasma upon cleavage or remains attached to activated FXIII. The aim of the present work was to study the structure of fr...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2007-06-01 00:00:00
abstract：:Prevention of a secondary response to factor IX by cyclophosphamide was attempted in an 11 year old patient with severe Christmas disease. An antibody to factor IX had been present for 4 years before immunosuppressive therapy was tried. Despite profound lymphopenia, synthesis of factor IX antibody was not depressed. T...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1976-08-31 00:00:00
abstract：:Graduated elastic compression stockings (GECS) are commonly used in the primary prevention of deep vein thrombosis (DVT); however, their role in preventing recurrent DVT and also post-thrombotic syndrome is less well established. The aim of this review was to investigate the effect of GECS after DVT. A literature sear...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,评审
doi：
更新日期：2006-10-01 00:00:00
abstract：:The administration of recombinant activated factor VII (rFVIIa) by continuous infusion has provided a safe and convenient alternative to bolus injections in haemophiliacs with inhibitors, but it has only been reported in a single case with congenital factor VII (FVII) deficiency. The results of 12 consecutive surgical...
journal_title：Thrombosis and haemostasis
pub_type： 临床试验,杂志文章,多中心研究
doi：10.1160/TH05-05-0342
更新日期：2005-12-01 00:00:00
abstract：:A group of 90 hemophiliacs who had been regularly treated with non virus-inactivated factor VIII or IX concentrates were studied in 1983. At that time 50 patients were HIV-1-antibody positive, 6 additional seroconversions occurred until 1985. 26 of the 50 patients seropositive in 1983 are currently asymptomatic. 4 pat...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1989-06-30 00:00:00
abstract：:Staphylokinase (SAK) expresses plasminogen activator (PA) activity by forming a complex with plasmin. The interaction between the plasmin-SAK complex and plasminogen was investigated using synthesized peptides, which were constructed according to the amino acid sequence of the SAK molecule. A synthetic nonadecapeptide...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2007-05-01 00:00:00
abstract：:Intraoperative high-dose aprotinin administration has been shown to reduce the intra-and postoperative blood loss in cardiac surgery. The haemostatic effect has been attributed to platelet preserving properties and to inhibition of contact activation reducing thrombotic and fibrinolytic activity during and after cardi...
journal_title：Thrombosis and haemostasis
pub_type： 临床试验,杂志文章,随机对照试验
doi：
更新日期：1995-05-01 00:00:00
abstract：:An amidrazonophenylalanine derivative, LB30057, inhibits the catalytic activity of thrombin potently by interaction with the active site of thrombin, and has high water solubility. In the present study, we evaluated the effect of LB30057 on the biological activities of thrombin at various tissues, and determined wheth...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：2003-01-01 00:00:00
abstract：BACKGROUND: Carotid atherosclerosis is an important cause of stroke. Intra-plaque haemorrhage (IPH) on magnetic resonance imaging (MRI) increases stroke risk. Development of IPH is only partly understood. Thrombin is an essential enzyme in haemostasis. Experimental animal studies have shown conflicting results on the r...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,多中心研究
doi：10.1055/s-0038-1666858
更新日期：2018-08-01 00:00:00
abstract：:Undoubtedly, platelets are key elements in the regulation of thrombosis and haemostasis. Along with their primary task to prevent blood loss from injured vessels, platelets have emerged as regulators of a variety of processes in the vasculature. Multiple challenges, from the contact and adhesion to subendothelial matr...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,评审
doi：10.1160/th07-01-0066
更新日期：2007-05-01 00:00:00
abstract：:An alternative method of uniting small diameter vessels to obtain tissue union while limiting the thrombogenic effect of suture placement at a vessel anastomosis involves the use of a thrombin based fibrin glue as a surgical sealant. This investigation addresses whether the in vitro application of a thrombin based glu...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章
doi：
更新日期：1997-08-01 00:00:00
abstract：:Fibrin sealant use in the United States has been limited because of the lack of a commercially available, government approved product. However, the significant need and usefulness of this material at the time of surgical operations has stimulated alternative sources of production. At the University of Virginia, the Bl...
journal_title：Thrombosis and haemostasis
pub_type： 杂志文章,评审
doi：
更新日期：1995-07-01 00:00:00
