| First Author | Moore SF | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 1468 |
| PubMed ID | 30728366 | Mgi Jnum | J:307441 |
| Mgi Id | MGI:6717996 | Doi | 10.1038/s41598-018-37012-9 |
| Citation | Moore SF, et al. (2019) Critical roles for the phosphatidylinositide 3-kinase isoforms p110beta and p110gamma in thrombopoietin-mediated priming of platelet function. Sci Rep 9(1):1468 |
| abstractText | Thrombopoietin (TPO) enhances platelet activation through activation of the tyrosine kinase; JAK2 and the lipid kinase phosphatidylinositide 3-kinase (PI3K). The aim of our study was to identify the PI3K isoforms involved in mediating the effect of TPO on platelet function and elucidate the underlying mechanism. We found that p110beta plays an essential role in TPO-mediated (i) priming of protease-activated receptor (PAR)-mediated integrin alphaIIbbeta3 activation and alpha-granule secretion, (ii) synergistic enhancement of PAR-mediated activation of the small GTPase RAP1, a regulator of integrin activation and (iii) phosphorylation of the PI3K effector Akt. More importantly, the synergistic effect of TPO on phosphorylation of extracellular-regulated kinase (ERK1/2) and thromboxane (TxA2) synthesis was dependent on both p110beta and p110gamma. p110beta inhibition/deletion, or inhibition of p110gamma, resulted in a partial reduction, whereas inhibiting both p110beta and p110gamma completely prevented the synergistic effect of TPO on ERK1/2 phosphorylation and TxA2 synthesis. The latter was ablated by inhibition of MEK, but not p38, confirming a role for ERK1/2 in regulating TPO-mediated increases in TxA2 synthesis. In conclusion, the synergistic effect of TPO on RAP1 and integrin activation is largely mediated by p110beta, whereas p110beta and p110gamma contribute to the effect of TPO on ERK1/2 phosphorylation and TxA2 formation. |
