PI 3-kinase signalling in platelets: the significance of synergistic, autocrine stimulation

Phosphoinositide S-kinases (PI 3Ks) play a keg role in regulation of intrac ellular signalling and cellular function, including cell proliferation, apo ptosis, chemotaxis, membrane trafficking and platelet activation. The PI 3K s are grouped into three classes on the basis on their structure and iii vi tro substrate specificity. Class I are activated by a variety of agonists w hich mediate their effect through tyrosine kinase-linked or G-protein-linke d receptors, In vivo class I PI 3Ks seem to preferentially phosphorylate th e D3 hydroxyls of the inositol moiety of PtdIns(4,5)P-2 to produce PtdIns(3 ,4,5)P-3. However, class II PI 3Ks preferentially phosphorylate the D3 hydr oxyl of PtdIns and PtdIns(4)P to produce PtdIns(3)P and PtdIns(3,4)P-2, res pectively. The late accumulation of PtdIns(3,4)P-2 has been suggested to pl ay an important role in irreversible platelet aggregation. In human platele ts the class II PI 3K isoform HsC2-PI 3K is activated in an integrin alpha( IIb)beta(3)+fibrinogen-dependent manner. Class III PI 3Ks phosphorylate Ptd Ins to produce PtdIns(3)P, which play a crucial role in vesicular trafficki ng, Recent work has suggested that crosstalk between individual receptors a nd their downstream signal pathways play a central role in PI 3K signalling responses. In this review, we will concentrate on recent advances regardin g the regulation of platelet PI 3Ks.