(A) Subunit composition and mechanism of activation of class IA and IB isoforms of phosphoinositide 3-kinase (PI3K). (B, left) Engagement of GPVI or αIIbβ3 activates of a Src family kinase (SFK), which phosphorylates tyrosine residues on an immunoreceptor tyrosine-based activation motif (ITAM)–containing subunit. Phosphotyrosine (pY) residues support binding and activation of spleen tyrosine kinase (Syk), which phosphorylates downstream adaptor molecules. The Src homology 2 (SH2) domains of the p85 subunit of PI3Kβ bind to pY-containing proteins, activating the p110β catalytic domain to convert PI(4,5)P2 to PI(3,4,5)P3 on the inner leaflet of the plasma membrane. The pleckstrin homology (PH)–domain-containing molecules 3-phosphoinositide–dependent protein kinase 1 (PDK1) and Akt bind to PI(3,4,5)P3, enabling PDK1-dependent activation of Akt and subsequent platelet activation. Canobbio et al found that platelets expressing a kinase dead form of PI3Kβ, or those that express a kinase dead form of PI3Kγ and are treated with a PI3Kβ-specific inhibitor, fail to respond to GPVI- or αIIbβ3-specific stimuli. These results indicate that GPVI- and αIIbβ3-dependent responses require p110β activity. (B, right) Binding of the G protein–coupled receptor (GPCR) ligands adenosine diphosphate (ADP) or thromboxane A2 (TxA2) activates PI3Kβ via an unknown mechanism, and also results in binding of the p101 subunit of PI3Kγ to dissociated Gβγ subunits, which activates the p110γ catalytic subunit to generate PI(3,4,5)P3 and induce Akt and platelet activation as described above. Canobbio et al found that platelets expressing kinase dead forms of either PI3Kβ or PI3Kγ fail to phosphorylate Akt but do aggregate in response to treatment with ADP. The same is true of platelets expressing a kinase dead form of PI3Kβ, or of those that express a kinase dead form of PI3Kγ and are treated with a PI3Kβ-specific inhibitor, in response to treatment with a TxA2 analog. These findings suggest that GPCRs can activate platelets in a manner that is independent of PI3Kγ and/or PI3Kβ activity, and that is independent of Akt activation.

(A) Subunit composition and mechanism of activation of class IA and IB isoforms of phosphoinositide 3-kinase (PI3K). (B, left) Engagement of GPVI or αIIbβ3 activates of a Src family kinase (SFK), which phosphorylates tyrosine residues on an immunoreceptor tyrosine-based activation motif (ITAM)–containing subunit. Phosphotyrosine (pY) residues support binding and activation of spleen tyrosine kinase (Syk), which phosphorylates downstream adaptor molecules. The Src homology 2 (SH2) domains of the p85 subunit of PI3Kβ bind to pY-containing proteins, activating the p110β catalytic domain to convert PI(4,5)P2 to PI(3,4,5)P3 on the inner leaflet of the plasma membrane. The pleckstrin homology (PH)–domain-containing molecules 3-phosphoinositide–dependent protein kinase 1 (PDK1) and Akt bind to PI(3,4,5)P3, enabling PDK1-dependent activation of Akt and subsequent platelet activation. Canobbio et al found that platelets expressing a kinase dead form of PI3Kβ, or those that express a kinase dead form of PI3Kγ and are treated with a PI3Kβ-specific inhibitor, fail to respond to GPVI- or αIIbβ3-specific stimuli. These results indicate that GPVI- and αIIbβ3-dependent responses require p110β activity. (B, right) Binding of the G protein–coupled receptor (GPCR) ligands adenosine diphosphate (ADP) or thromboxane A2 (TxA2) activates PI3Kβ via an unknown mechanism, and also results in binding of the p101 subunit of PI3Kγ to dissociated Gβγ subunits, which activates the p110γ catalytic subunit to generate PI(3,4,5)P3 and induce Akt and platelet activation as described above. Canobbio et al found that platelets expressing kinase dead forms of either PI3Kβ or PI3Kγ fail to phosphorylate Akt but do aggregate in response to treatment with ADP. The same is true of platelets expressing a kinase dead form of PI3Kβ, or of those that express a kinase dead form of PI3Kγ and are treated with a PI3Kβ-specific inhibitor, in response to treatment with a TxA2 analog. These findings suggest that GPCRs can activate platelets in a manner that is independent of PI3Kγ and/or PI3Kβ activity, and that is independent of Akt activation.

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