Blood Journal
Leading the way in experimental and clinical research in hematology

IκB kinase (IKK) phosphorylation of SNAP-23 controls platelet secretion

  1. Zubair A. Karim1,
  2. Jinchao Zhang1,
  3. Meenakshi Banerjee1,
  4. Michael C. Chicka1,
  5. Rania Al Hawas1,
  6. Tara R. Hamilton1,
  7. Paul A. Roche2, and
  8. Sidney W. Whiteheart1,*
  1. 1 Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, United States;
  2. 2 Experimental Immunology Branch, National Cancer Institute, Bethesda, MD, United States
  1. * Corresponding author; email: whitehe{at}

Key points

  • Nongenomic role for IkappaB kinase (IKK) in platelet secretion: IKK phosphorylates SNAP-23, which affects granule-plasma membrane fusion.

  • Pharmacologic inhibition or deletion of platelet IKK affects bleeding times suggesting the utility of IKK inhibitors as anti-thrombotics.


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-SNARE occurs upon activation of known elements of the platelet signaling cascades (i.e. Phospholipase C, [Ca2+]i, Protein Kinase C) and requires IκB Kinase β (IKKβ. Other elements of the NFκB/IκB cascade (i.e. IKKα, β, γ/NEMO and CARMA/MALT1/Bcl10 complex) are present in anucleate platelets and IκB is phosphorylated upon activation suggesting that this pathway is active in platelets and implying a nongenomic role for IKK. Inhibition of IKKβ either pharmacologically (with BMS-345541, BAY11-7082, or TPCA-1) or by genetic manipulation (Platelet Factor 4 Cre::IKKβflox/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 IKKβ knockout mice showed that blocking IKKβ activity significantly prolonged tail-bleeding times suggesting that currently available IKK inhibitors may affect hemostasis.

  • Submitted November 30, 2012.
  • Accepted April 12, 2013.