IkB kinase phosphorylation of SNAP-23 controls platelet secretion

Zubair A. Karim, Jinchao Zhang, Meenakshi Banerjee, Michael C. Chicka, Rania Al Hawas, Tara R. Hamilton, Paul A. Roche, Sidney W. Whiteheart

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

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, [Ca2+]i, protein kinase C) and requires IκB kinase (IKK)-β. Other elements of the nuclear factor kB/IkB cascade (ie, IKK-α,-β,-γ/NEMO and CARMA/MALT1/Bcl10 complex) are present in anucleate platelets and IkB is phosphorylated upon activation, suggesting that this pathway is active in platelets and implying a nongenomic role for IKK. Inhibition of IKK-β, either pharmacologically (with BMS-345541, BAY11-7082, or TPCA-1) or by genetic manipulation (platelet factor 4 Cre:IKK-βflox/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-β knockout mice showed that blocking IKK-β activity significantly prolonged tail bleeding times, suggesting that currently available IKK inhibitors may affect hemostasis.

Original languageEnglish (US)
Pages (from-to)4567-4574
Number of pages8
JournalBlood
Volume121
Issue number22
DOIs
StatePublished - May 30 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint

Dive into the research topics of 'IkB kinase phosphorylation of SNAP-23 controls platelet secretion'. Together they form a unique fingerprint.

Cite this