PI 3-kinase signalling in platelets: the significance of synergistic, autocrine stimulation.
Phosphoinositide 3-kinases (PI 3Ks) play a key role in regulation of intracellular signalling and cellular function, including cell proliferation, apoptosis, chemotaxis, membrane trafficking and platelet activation. The PI 3Ks are grouped into three classes on the basis on their structure and in vitro substrate specificity. Class I are activated by a variety of agonists which mediate their effect through tyrosine kinase-linked or G-protein-linked receptors. In vivo class I PI 3Ks seem to preferentially phosphorylate the D3 hydroxyls of the inositol moiety of PtdIns(4,5)P2 to produce PtdIns(3,4,5)P3. However, class II PI 3Ks preferentially phosphorylate the D3 hydroxyl of PtdIns and PtdIns(4)P to produce PtdIns(3)P and PtdIns(3,4)P2, respectively. The late accumulation of PtdIns(3,4)P2 has been suggested to play an important role in irreversible platelet aggregation. In human platelets 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 PtdIns to produce PtdIns(3)P, which play a crucial role in vesicular trafficking. Recent work has suggested that crosstalk between individual receptors and their downstream signal pathways play a central role in PI 3K signalling responses. In this review, we will concentrate on recent advances regarding the regulation of platelet PI 3Ks.
Selheim
F
F
Department of Biochemistry and Molecular Biology, University of Bergen, Norway. Frode.Selheim@pki.uib.no
Holmsen
H
H
Vassbotn
F S
FS
D019898:Autocrine Communication; D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000145:classification / Q000378:metabolism / Q000502:physiology*; D010716:Phosphatidylinositols / Q000096:biosynthesis / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction
D010716:Phosphatidylinositols; D019869:Phosphatidylinositol 3-Kinases