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Phosphoinositide 3-kinase in Health and Disease pp 203–224Cite as

PI 3-Kinase p110β Regulation of Platelet Integrin αIIbβ3

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 346))

Abstract

Hemopoietic cells express relatively high levels of the type I phosphoinositide (PI) 3-kinase isoforms, with p110δ and γ exhibiting specialized signaling functions in neutrophils, monocytes, mast cells, and lymphocytes. In platelets, p110β appears to be the dominant PI 3-kinase isoform regulating platelet activation, irrespective of the nature of the primary platelet activating stimulus. Based on findings with isoform-selective p110β pharmacological inhibitors and more recently with p110β–deficient platelets, p110β appears to primarily signal downstream of Gi- and tyrosine kinase-coupled receptors. Functionally, inhibition of p110β kinase function leads to a marked defect in integrin αIIbβ3 adhesion and reduced platelet thrombus formation in vivo. This defect in platelet adhesive function is not associated with increased bleeding, suggesting that therapeutic targeting of p110β may represent a safe approach to reduce thrombotic complications in patients with cardiovascular disease.

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Abbreviations

3-PPIs:

3-Phosphorylated phosphoinositides

ADP:

Adenosine diphosphate

CalDAG-GEF1:

Calcium and DAG-dependent guanine nucleotide exchange factor

DAG:

Diacylglycerol

fMLP:

formyl-Met-Leu-Phe

GP:

Glycoprotein

GPCR:

G-protein coupled receptor

IP3:

Inositol (1,4,5)-triphosphate

ITAM:

Immunoreceptor tyrosine-based activation motif

PAR:

Protease-activated receptor

PH:

Pleckstrin homology

PI:

Phosphoinositide

PI(3,4)P2 :

Phosphoinositide (3,4)-biphosphate

PI(3,4,5)P3 :

Phosphoinositide (3,4,5)-triphosphate

PKC:

Protein kinase C

PLC:

Phospholipase C

RIAM:

Rap1-GTP interacting adapter molecule

TXA2:

Thromboxane A2

VWF:

von Willebrand factor

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  1. Australian Centre for Blood Diseases, Alfred Medical Research and Education Precinct (AMREP), Monash University, 6th Level Burnet Building, 89 Commercial Road, Melbourne, VIC, 3004, Australia

    Shaun P. Jackson & Simone M. Schoenwaelder

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    Christian Rommel

  2. , Institute of Cancer and the London Schoo, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom

    Bart Vanhaesebroeck

  3. , Dept. Molecular & Exp. Medicine, Scripps Research Institute, N. Torrey Pines Road 10550, La Jolla, 92037, California, USA

    Peter K. Vogt

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Jackson, S.P., Schoenwaelder, S.M. (2010). PI 3-Kinase p110β Regulation of Platelet Integrin αIIbβ3 . In: Rommel, C., Vanhaesebroeck, B., Vogt, P. (eds) Phosphoinositide 3-kinase in Health and Disease. Current Topics in Microbiology and Immunology, vol 346. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_61

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