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Regulation of I‐kappa‐B kinase (IKK) Pathway by CARMA 1•Bcl‐10•MALT‐1 (CBM) Complex Promotes SNARE Complex Formation and Secretion in Platelets
Author(s) -
Banerjee Meenakshi,
Karim Zubair A.,
Zhang Jinchao,
Whiteheart Sidney W.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.986.1
Subject(s) - iκb kinase , microbiology and biotechnology , phosphorylation , signal transduction , platelet activation , kinase , secretion , chemistry , biology , platelet , biochemistry , nf κb , immunology
In deciphering the underlying mechanisms of how the platelet SNARE complex machinery modulates thrombosis and granule release, we have discovered that agonist‐dependent stimulation of platelets leads to the phosphorylation of the t‐SNARE, SNAP‐23, at Ser95, by I‐kappa‐B Kinase (IKK) thus playing a key role in SNARE complex assembly and secretion. The presence of the IKK complex (IKKα, IKKβ, IKKγ) and its agonist‐dependent phosphorylation, in anucleate platelets implies for a unique non‐transcriptional activity. Inhibition of IKK using inhibitors showed that both SNAP‐23 phosphorylation and platelet secretion were affected without adversely affecting calcium mobilization, cytoskeletal changes, or tyrosine kinase signaling. Corroborating these studies, in vivo studies in mice treated with IKK inhibitors significantly prolong tail bleeding times confirming secretion defect. Further analysis of the upstream elements of the pathway suggests that CARMA1‐Bcl10‐MALT‐1 (CBM) proteins are present and their differential translocation to lipid rafts, which abound in SNAP‐23, upon agonist stimulation in platelets emphasizes the novel regulation of the CBM‐IKK‐SNAP‐23 pathway in promoting SNARE complex formation, platelet exocytosis and possibly in mediating platelet inflammatory responses. Collectively these data implicate CBM‐IKK‐SNAP‐23 signaling cascade in controlling platelet thrombosis with long‐term studies aimed at developing these as anti‐thrombotic therapeutics. (Supported by HL56652 and HL091893 to S. W. W)