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rdf:type |
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lifeskim:mentions |
umls-concept:C0001516,
umls-concept:C0005821,
umls-concept:C0016011,
umls-concept:C0020792,
umls-concept:C0031621,
umls-concept:C0037083,
umls-concept:C0441712,
umls-concept:C0542341,
umls-concept:C1710082,
umls-concept:C1710548,
umls-concept:C1998811
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pubmed:issue |
39
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pubmed:dateCreated |
2007-9-24
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pubmed:abstractText |
Phosphoinositide (PI) 3-kinases play an important role in regulating the adhesive function of a variety of cell types through affinity modulation of integrins. Two type I PI 3-kinase isoforms (p110 beta and p110 gamma) have been implicated in G(i)-dependent integrin alpha(IIb)beta(3) regulation in platelets, however, the mechanisms by which they coordinate their signaling function remains unknown. By employing isoform-selective PI 3-kinase inhibitors and knock-out mouse models we have identified a unique mechanism of PI 3-kinase signaling co-operativity in platelets. We demonstrate that p110 beta is primarily responsible for G(i)-dependent phosphatidylinositol 3,4-bisphosphate (PI(3,4)P(2)) production in ADP-stimulated platelets and is linked to the activation of Rap1b and AKT. In contrast, defective integrin alpha(IIb)beta(3) activation in p110 gamma(-/-) platelets was not associated with alterations in the levels of PI(3,4)P(2) or active Rap1b/AKT. Analysis of the effects of active site pharmacological inhibitors confirmed that p110 gamma principally regulated integrin alpha(IIb)beta(3) activation through a non-catalytic signaling mechanism. Inhibition of the kinase function of PI 3-kinases, combined with deletion of p110 gamma, led to a major reduction in integrin alpha(IIb)beta(3) activation, resulting in a profound defect in platelet aggregation, hemostatic plug formation, and arterial thrombosis. These studies demonstrate a kinase-independent signaling function for p110 gamma in platelets. Moreover, they demonstrate that the combined catalytic and non-catalytic signaling function of p110 beta and p110 gamma is critical for P2Y(12)/G(i)-dependent integrin alpha(IIb)beta(3) regulation. These findings have potentially important implications for the rationale design of novel antiplatelet therapies targeting PI 3-kinase signaling pathways.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Diphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/GTP-Binding Protein alpha...,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/P2ry12 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol Phosphates,
http://linkedlifedata.com/resource/pubmed/chemical/Platelet Glycoprotein GPIIb-IIIa...,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Purinergic P2 Receptor Agonists,
http://linkedlifedata.com/resource/pubmed/chemical/Rap1b protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Purinergic P2,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Purinergic P2Y12,
http://linkedlifedata.com/resource/pubmed/chemical/phosphatidylinositol 3,4-diphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/rap GTP-Binding Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0021-9258
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pubmed:author |
pubmed-author:AndersonKarenK,
pubmed-author:ChanSiew MeiSM,
pubmed-author:GachetChristianC,
pubmed-author:JacksonShaun PSP,
pubmed-author:KauffensteinGillesG,
pubmed-author:KendallJackieJ,
pubmed-author:ManginPierreP,
pubmed-author:MaxwellMhairi JMJ,
pubmed-author:MulchandaniMeghaM,
pubmed-author:OnoAkikoA,
pubmed-author:RewcastleGordon WGW,
pubmed-author:SalemHatem HHH,
pubmed-author:SchoenwaelderSimone MSM,
pubmed-author:SturgeonSharelleS,
pubmed-author:TurnbullShannonS
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pubmed:issnType |
Print
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pubmed:day |
28
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pubmed:volume |
282
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
28648-58
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:17673465-Adenosine Diphosphate,
pubmed-meshheading:17673465-Animals,
pubmed-meshheading:17673465-Blood Platelets,
pubmed-meshheading:17673465-Enzyme Inhibitors,
pubmed-meshheading:17673465-GTP-Binding Protein alpha Subunits, Gi-Go,
pubmed-meshheading:17673465-Isoenzymes,
pubmed-meshheading:17673465-Membrane Proteins,
pubmed-meshheading:17673465-Mice,
pubmed-meshheading:17673465-Mice, Knockout,
pubmed-meshheading:17673465-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:17673465-Phosphatidylinositol Phosphates,
pubmed-meshheading:17673465-Platelet Adhesiveness,
pubmed-meshheading:17673465-Platelet Glycoprotein GPIIb-IIIa Complex,
pubmed-meshheading:17673465-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:17673465-Purinergic P2 Receptor Agonists,
pubmed-meshheading:17673465-Receptors, Purinergic P2,
pubmed-meshheading:17673465-Receptors, Purinergic P2Y12,
pubmed-meshheading:17673465-Second Messenger Systems,
pubmed-meshheading:17673465-rap GTP-Binding Proteins
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pubmed:year |
2007
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pubmed:articleTitle |
Identification of a unique co-operative phosphoinositide 3-kinase signaling mechanism regulating integrin alpha IIb beta 3 adhesive function in platelets.
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pubmed:affiliation |
Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Victoria, Australia.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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