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J Biol Chem. 2013 Nov 29;288(48):34352-63. doi: 10.1074/jbc.M113.459750. Epub 2013 Oct 16.

Wiskott-Aldrich syndrome protein (WASp) controls the delivery of platelet transforming growth factor-β1.

Author information

1
From the Division of Translational Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.

Abstract

Platelets are immunologically competent cells containing cytokines such as TGF-β1 that regulate cell-mediated immunity. However, the mechanisms underlying cytokine secretion from platelets are undefined. The Wiskott-Aldrich syndrome protein (WASp) regulates actin polymerization in nucleated hematopoietic cells but has other role(s) in platelets. WASp-null (WASp(-/-)) platelets stimulated with a PAR-4 receptor agonist had increased TGF-β1 release compared with WT platelets; inhibiting WASp function with wiskostatin augmented TRAP-induced TGF-β1 release in human platelets. TGF-β1 release is dissociated from α-granule secretion (P-selectin up-regulation) and occurs more gradually, with ∼10-15% released after 30-60 min. Blockade of Src family kinase-mediated WASp Tyr-291/Tyr-293 phosphorylation increased TGF-β1 release, with no additive effect in WASp(-/-) platelets, signifying that phosphorylation is critical for WASp-limited TGF-β1 secretion. Inhibiting F-actin assembly with cytochalasin D enhanced secretion in WT platelets and further increased TGF-β1 release in WASp(-/-) platelets, indicating that WASp and actin assembly independently regulate TGF-β1 release. A permeabilized platelet model was used to test the role of upstream small GTPases in TGF-β1 release. N17Cdc42, but not Rac1 mutants, increased TGF-β1 secretion and abrogated WASp phosphorylation. We conclude that WASp function restricts TGF-β1 secretion in a Cdc42- and Src family kinase-dependent manner and independently of actin assembly.

KEYWORDS:

Cytokine; Extracellular Matrix; Platelets; Signal Transduction; Signaling

PMID:
24133214
PMCID:
PMC3843050
DOI:
10.1074/jbc.M113.459750
[Indexed for MEDLINE]
Free PMC Article
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