Phosphoinositide 3-kinases and the regulation of platelet function.
A clear understanding of the role of PI (phosphoinositide) 3-kinases in supporting the haemostatic function of platelets has been slow to evolve. In fact, insight into the roles of individual PI 3-kinase isoforms in platelet function remains rudimentary. However, based on in vitro studies using wortmannin and LY294002, there is evidence for an important role for PI 3-kinases in regulating a broad range of functional platelet responses, including primary platelet adhesion, cytoskeletal remodelling and platelet aggregation. One of the critical platelet responses involves affinity regulation of the major platelet integrin alphaIIbbeta3, the primary receptor mediating platelet aggregation and thrombus growth. The input signals regulating integrin alphaIIbbeta3 can be divided into three main groups: (1) G(q)-coupled receptors linked to the activation of PLCbeta (phospholipase Cbeta); (2) G(i)-coupled receptors linked to the regulation of adenylate cyclase and Rap1b; and (3) adhesion receptor signalling involving Src kinase-dependent activation of PLCgamma isoforms. PI 3-kinases have not been demonstrated to play a critical role in G(q)-dependent platelet activation; however, one or more PI 3-kinase isoforms appears to be important for G(i)-dependent activation of Rap1b and adhesion receptor activation of PLCgamma isoforms. Thus distinct co-operative PI 3-kinase signalling mechanisms appear to play an important role in regulating the adhesive function of integrin alphaIIbbeta3.
Jackson
S P
SP
Australian Centre for Blood Diseases, Department of Medicine, Monash Medical School, Box Hill Hospital, Box Hill, Victoria, Australia. shaun.jackson@med.monash.edu.au
Yap
C L
CL
Anderson
K E
KE
D000818:Animals; D001792:Blood Platelets / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion; D002455:Cell Division; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D020033:Protein Isoforms; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D016023:Integrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D020033:Protein Isoforms; D019869:Phosphatidylinositol 3-Kinases