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  1. Article ; Online: IκB kinase phosphorylation of SNAP-23 controls platelet secretion.

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

    Blood

    2013  Volume 121, Issue 22, Page(s) 4567–4574

    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- ... ...

    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, [Ca(2+)]i, protein kinase C) and requires IκB kinase (IKK)-β. Other elements of the nuclear factor κB/IκB cascade (ie, IKK-α,-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 IKK-β, either pharmacologically (with BMS-345541, BAY11-7082, or TPCA-1) or by genetic manipulation (platelet factor 4 Cre:IKK-β(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-β knockout mice showed that blocking IKK-β activity significantly prolonged tail bleeding times, suggesting that currently available IKK inhibitors may affect hemostasis.
    MeSH term(s) Animals ; Blood Platelets/metabolism ; Cytoplasmic Granules/metabolism ; Enzyme Activation/physiology ; Hemostasis/physiology ; I-kappa B Kinase/genetics ; I-kappa B Kinase/metabolism ; Membrane Fusion/physiology ; Mice ; Mice, Knockout ; Phosphorylation/physiology ; Platelet Activation/physiology ; Qb-SNARE Proteins/metabolism ; Qc-SNARE Proteins/metabolism ; SNARE Proteins/metabolism ; Signal Transduction/physiology
    Chemical Substances Qb-SNARE Proteins ; Qc-SNARE Proteins ; SNARE Proteins ; Snap23 protein, mouse ; I-kappa B Kinase (EC 2.7.11.10)
    Language English
    Publishing date 2013-04-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2012-11-470468
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: Syntaxin-11, but not syntaxin-2 or syntaxin-4, is required for platelet secretion.

    Ye, Shaojing / Karim, Zubair A / Al Hawas, Rania / Pessin, Jeffery E / Filipovich, Alexandra H / Whiteheart, Sidney W

    Blood

    2012  Volume 120, Issue 12, Page(s) 2484–2492

    Abstract: The platelet release reaction plays a critical role in thrombosis and contributes to the events that follow hemostasis. Previous studies have shown that platelet secretion is mediated by Soluble NSF Attachment Protein Receptor (SNARE) proteins from ... ...

    Abstract The platelet release reaction plays a critical role in thrombosis and contributes to the events that follow hemostasis. Previous studies have shown that platelet secretion is mediated by Soluble NSF Attachment Protein Receptor (SNARE) proteins from granule and plasma membranes. The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. Although VAMP-8 (v-SNARE) and SNAP-23 (a t-SNARE class) are important for platelet secretion, the identity of the functional syntaxin (another t-SNARE class) has been controversial. Previous studies using anti-syntaxin Abs in permeabilized platelets have suggested roles for both syntaxin-2 and syntaxin-4. In the present study, we tested these conclusions using platelets from syntaxin-knockout mouse strains and from a Familial Hemophagocytic Lymphohistiocytosis type 4 (FHL4) patient. Platelets from syntaxin-2 and syntaxin-4 single- or double-knockout mice had no secretion defect. Platelets from a FHL4 patient deficient in syntaxin-11 had a robust defect in agonist-induced secretion although their morphology, activation, and cargo levels appeared normal. Semiquantitative Western blotting showed that syntaxin-11 is the more abundant syntaxin in both human and murine platelets. Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. The results of the present study indicate that syntaxin-11, but not syntaxin-2 or syntaxin-4, is required for platelet exocytosis.
    MeSH term(s) Animals ; Blood Platelets/metabolism ; Blood Platelets/ultrastructure ; Cell Membrane/metabolism ; Cytoplasmic Granules/metabolism ; Exocytosis/physiology ; Female ; Humans ; Immunoprecipitation ; Lymphohistiocytosis, Hemophagocytic/metabolism ; Lymphohistiocytosis, Hemophagocytic/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Platelet Aggregation ; Qa-SNARE Proteins/genetics ; Qa-SNARE Proteins/metabolism ; Qa-SNARE Proteins/physiology ; Syntaxin 1/physiology
    Chemical Substances Qa-SNARE Proteins ; STX11 protein, human ; Syntaxin 1
    Language English
    Publishing date 2012-07-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2012-05-430603
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  3. Article ; Online: Munc18b/STXBP2 is required for platelet secretion.

    Al Hawas, Rania / Ren, Qiansheng / Ye, Shaojing / Karim, Zubair A / Filipovich, Alexandra H / Whiteheart, Sidney W

    Blood

    2012  Volume 120, Issue 12, Page(s) 2493–2500

    Abstract: Platelets are vital for hemostasis because they release their granule contents in response to vascular damage. Platelet exocytosis is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), whose interactions are ... ...

    Abstract Platelets are vital for hemostasis because they release their granule contents in response to vascular damage. Platelet exocytosis is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), whose interactions are governed by regulators, eg, Sec/Munc18 proteins. These proteins chaperone syntaxin t-SNAREs and are required for exocytosis. Platelets contain 3 Munc18 isoforms: Munc18a, Munc18b, and Munc18c. We report that Munc18b is the major isoform and is required for platelet secretion. Familial hemophagocytic lymphohistiocytosis type 5 (FHL5) is caused by defects in the Munc18b/STXBP2 gene. We confirm a previous report showing that platelets from FHL5 patients have defective secretion. Serotonin, ADP/ATP, and platelet factor 4 release was profoundly affected in the 2 biallelic patients and partially in a heterozygous patient. Release of lysosomal contents was only affected in the biallelic platelets. Platelets from the FHL5 biallelic patients showed decreased Munc18b and syntaxin-11 levels were significantly reduced; other syntaxins were unaffected. Munc18b formed complexes with syntaxin-11, SNAP-23, and vesicle-associated membrane protein-8 in human platelets. Other potential secretion regulators, Munc13-4 and Rab27, were also found associated. These data demonstrate a key role for Munc18b, perhaps as a limiting factor, in platelet exocytosis and suggest that it regulates syntaxin-11.
    MeSH term(s) Blood Platelets/metabolism ; Blood Platelets/ultrastructure ; Blotting, Western ; Case-Control Studies ; Cytoplasmic Granules/metabolism ; Exocytosis/physiology ; Flow Cytometry ; Humans ; Immunoprecipitation ; Lymphohistiocytosis, Hemophagocytic/genetics ; Lymphohistiocytosis, Hemophagocytic/metabolism ; Lymphohistiocytosis, Hemophagocytic/pathology ; Munc18 Proteins/metabolism ; Platelet Aggregation/physiology ; Qa-SNARE Proteins/metabolism ; SNARE Proteins/metabolism
    Chemical Substances Munc18 Proteins ; Qa-SNARE Proteins ; SNARE Proteins ; STX11 protein, human
    Language English
    Publishing date 2012-07-12
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2012-05-430629
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.140: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
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    Zs.MO 364: Show issues

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