| First Author | Karim ZA | Year | 2013 |
| Journal | Blood | Volume | 121 |
| Issue | 22 | Pages | 4567-74 |
| PubMed ID | 23613522 | Mgi Jnum | J:198957 |
| Mgi Id | MGI:5499946 | Doi | 10.1182/blood-2012-11-470468 |
| Citation | Karim ZA, et al. (2013) IkappaB kinase phosphorylation of SNAP-23 controls platelet secretion. Blood 121(22):4567-74 |
| abstractText | Platelet secretion plays a key role in thrombosis, thus the platelet secretory machinery offers a unique target to modulate hemostasis. We report the regulation of platelet secretion via phosphorylation of SNAP-23 at Ser95. Phosphorylation of this t-soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) occurs upon activation of known elements of the platelet signaling cascades (ie, phospholipase C, [Ca(2+)]i, protein kinase C) and requires IkappaB kinase (IKK)-beta. Other elements of the nuclear factor kappaB/IkappaB cascade (ie, IKK-alpha,-beta,-gamma/NEMO and CARMA/MALT1/Bcl10 complex) are present in anucleate platelets and IkappaB is phosphorylated upon activation, suggesting that this pathway is active in platelets and implying a nongenomic role for IKK. Inhibition of IKK-beta, either pharmacologically (with BMS-345541, BAY11-7082, or TPCA-1) or by genetic manipulation (platelet factor 4 Cre:IKK-beta(flox/flox)), blocked SNAP-23 phosphorylation, platelet secretion, and SNARE complex formation; but, had no effect on platelet morphology or other metrics of platelet activation. Consistently, SNAP-23 phosphorylation enhanced membrane fusion of SNARE-containing proteoliposomes. In vivo studies with IKK inhibitors or platelet-specific IKK-beta knockout mice showed that blocking IKK-beta activity significantly prolonged tail bleeding times, suggesting that currently available IKK inhibitors may affect hemostasis. |
