Role of the p110delta PI 3-kinase in integrin and ITAM receptor signalling in platelets.
We have investigated the function of the p110delta catalytic subunit of phosphoinositide 3-kinase (PI 3-kinase) in platelets using p110delta knock-out (p110delta(-/-)) mice and p110delta knock-in (p110delta(D910A/D910A)) mice, which express a catalytically inactive form of the enzyme. Aggregation to threshold concentrations of the GPVI-specific agonist, CRP, was partially reduced in p110delta(-/-) and p110delta(D910A/D910A) platelets. This inhibition was overcome by higher concentrations of CRP. The degree of inhibition was considerably weaker than that induced by LY294002 and wortmannin, which inhibit all isoforms of PI 3-kinase. p110delta(-/-) platelets showed decreased spreading on fibrinogen- or von Willebrand factor (VWF)-coated surfaces under static conditions, whereas they spread normally on collagen. LY294002 had a more pronounced inhibitory effect on spreading on all three surfaces. Adhesion and aggregate formation of p110delta(-/-) platelets to collagen or fibrinogen/VWF at intermediate/high rates of shear were normal. This study demonstrates a minor role for the p110delta catalytic subunit in mediating platelet activation by the collagen receptor GPVI and integrin alphaIIbeta3. The more pronounced inhibitory effect of LY294002 and wortmannin indicates that other isoforms of PI 3-kinase play a more significant role in signalling by the two platelet glycoprotein receptors.
Senis
Yotis A
YA
Centre for Cardiovascular Sciences, Division of Medical Sciences, Institute of Biomedical Research, Wolfson Drive, The Medical School, University of Birmingham, Edgbaston, Birmingham, UK. y.senis@bham.ac.uk
Atkinson
Ben T
BT
Pearce
Andrew C
AC
Wonerow
Peter
P
Auger
Jocelyn M
JM
Okkenhaug
Klaus
K
Pearce
Wayne
W
Vigorito
Elena
E
Vanhaesebroeck
Bart
B
Turner
Martin
M
Watson
Steve P
SP
D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000201:enzymology* / Q000502:physiology; D002097:C-Reactive Protein / Q000187:drug effects; D048430:Cell Shape; D058534:Class I Phosphatidylinositol 3-Kinases; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D015398:Signal Transduction
D002097:C-Reactive Protein; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; C421683:Pik3cd protein, mouse