UCL University College London Eprints
UCL Eprints collects the work of UCL researchers and makes it freely available over the web, helping the worldwide scholarly community to discover UCL research. Institutional repositories like UCL Eprints complement the traditional academic publishing and scholarly communications processes. They raise the visibility of research and help to maximise its impact. UCL researchers are encouraged to deposit a copy of each journal article, conference paper, working paper, and any other research output, in the UCL Eprints at the earliest opportunity, ensuring that their research reaches as wide an audience as possible.
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Platelet PI3Kβ and GSK3 regulate thrombus stability at high-shear rate. - Laurent, PA; Séverin, S; Hechler, B; Vanhaesebroeck, B; Payrastre, B; Gratacap, MP
Class IA phosphoinositide 3-kinase β (PI3Kβ) is considered as a potential drug target in arterial thrombosis, a major cause of death worldwide. Here, we show that a striking phenotype of mice with selective p110β deletion in the megakaryocyte lineage is thrombus instability at high-shear rate, an effect not detected in absence of p110α in platelets. The high-shear rate-dependent thrombus instability in the absence of p110β is observed both ex vivo and in vivo with the formation of platelet emboli. Moreover, PI3Kβ is required for the recruitment of new platelets to a growing thrombus when a pathological high-shear is applied. Treatment...
A new TIPE of phosphoinositide regulator in cancer. - Moniz, LS; Vanhaesebroeck, B
Specific phosphoinositide lipids promote cell growth and cancer. In this issue of Cancer Cell, Fayngerts and colleagues demonstrate that the TIPE3 protein enhances PtdIns(4,5)P2 and PtdIns(3,4,5)P3, is overexpressed in certain cancers, and promotes tumorigenesis. TIPE3 can act as a lipid transfer protein and may constitute a novel phosphoinositide metabolism regulator.
Phosphoinositide 3-kinase β mediates microvascular endothelial repair of thrombotic microangiopathy. - Haddad, G; Zhabyeyev, P; Farhan, M; Zhu, LF; Kassiri, Z; Rayner, DC; Vanhaesebroeck, B; Oudit, GY; Murray, AG
Thrombotic microangiopathy (TMA) commonly involves injury of kidney glomerular endothelial cells (ECs) and fibrin occlusion of the capillaries. The mechanisms underlying repair of the microvasculature and recovery of kidney function are poorly defined. In the developing vasculature, the phosphoinositide 3-kinase (PI3K) α isoform integrates many growth factor cues. However, the role of individual isoforms in repair of the established vasculature is unclear. We found that postnatal endothelial deletion of PI3Kβ sensitizes mice to lethal acute kidney failure after TMA injury. In vitro, PI3Kβ-deficient ECs show reduced angiogenic invasion of fibrin matrix with unaltered sensitivity to proapoptotic stress compared with wild-type...
Phosphoinositide 3-kinases p110α and p110β have differential roles in insulin-like growth factor-1-mediated akt phosphorylation and platelet priming - Blair, TA; Moore, SF; Williams, CM; Poole, AW; Hers, I; Vanhaesebroeck, B
Objective - Platelet hyperactivity is a contributing factor in the pathogenesis of cardiovascular disease and can be induced by elevated levels of circulating growth factors, such as insulin-like growth factor-1 (IGF-1). IGF-1 is a primer that cannot stimulate platelet activation by itself, but in combination with physiological stimuli can potentiate platelet functional responses via a phosphoinositide 3-kinase-dependent mechanism. In this study, we explored the role of the phosphoinositide 3-kinase p110α isoform in IGF-1-mediated enhancement of platelet function. Approach And Results - Using a platelet-specific p110α knockout murine model, we demonstrate that genetic deletion, similar to pharmacological inactivation of p110α, did...
Structure-based design and functional studies of novel noroviral 3C protease chimaeras offer insights into substrate specificity. - Herod, MR; Prince, CA; Skilton, RJ; Ward, VK; Cooper, JB; Clarke, IN
The norovirus NS6 protease is a key target for anti-viral drug development. Noroviruses encode a 2200 amino acid polyprotein which is cleaved by this critical protease at five defined boundary substrates into six mature non-structural (NS) proteins. Studies of the human norovirus (HNV) NS6 protease, in the context of a full ORF1 polyprotein, have been severely hampered because HNVs are not culturable. Thus, investigations into the HNV NS6 protease have been largely restricted to in vitro assays using Escherichia coli-expressed, purified enzyme. The NS6 protease is formed of two distinct domains joined by a linking loop. Structural data suggest that domain...
Renal Fanconi syndrome: taking a proximal look at the nephron. - Klootwijk, ED; Reichold, M; Unwin, RJ; Kleta, R; Warth, R; Bockenhauer, D
Renal Fanconi syndrome (RFS) refers to the generalized dysfunction of the proximal tubule (PT) (Kleta R. Fanconi or not Fanconi? Lowe syndrome revisited. Clin J Am Soc Nephrol 2008; 3: 1244-1245). In its isolated form, RFS only affects the PT, but not the other nephron segments. The study of isolated RFS can thus provide specific insights into the function of the PT. In a recent paper, Klootwijk et al. investigated one such form of isolated RFS and revealed the underlying molecular basis (Klootwijk ED, Reichold M, Helip-Wooley A et al. Mistargeting of peroxisomal EHHADH and inherited renal Fanconi's syndrome. N...