| First Author | Kim H | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 48 | Pages | 34352-63 |
| PubMed ID | 24133214 | Mgi Jnum | J:204969 |
| Mgi Id | MGI:5543828 | Doi | 10.1074/jbc.M113.459750 |
| Citation | Kim H, et al. (2013) Wiskott-Aldrich syndrome protein (WASp) controls the delivery of platelet transforming growth factor-beta1. J Biol Chem 288(48):34352-63 |
| abstractText | Platelets are immunologically competent cells containing cytokines such as TGF-beta1 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-beta1 release compared with WT platelets; inhibiting WASp function with wiskostatin augmented TRAP-induced TGF-beta1 release in human platelets. TGF-beta1 release is dissociated from alpha-granule secretion (P-selectin up-regulation) and occurs more gradually, with approximately 10-15% released after 30-60 min. Blockade of Src family kinase-mediated WASp Tyr-291/Tyr-293 phosphorylation increased TGF-beta1 release, with no additive effect in WASp(-/-) platelets, signifying that phosphorylation is critical for WASp-limited TGF-beta1 secretion. Inhibiting F-actin assembly with cytochalasin D enhanced secretion in WT platelets and further increased TGF-beta1 release in WASp(-/-) platelets, indicating that WASp and actin assembly independently regulate TGF-beta1 release. A permeabilized platelet model was used to test the role of upstream small GTPases in TGF-beta1 release. N17Cdc42, but not Rac1 mutants, increased TGF-beta1 secretion and abrogated WASp phosphorylation. We conclude that WASp function restricts TGF-beta1 secretion in a Cdc42- and Src family kinase-dependent manner and independently of actin assembly. |
