Integrin α_IIbβ₃ signals lead cofilin to accelerate platelet actin dynamics

Abstract

Cofilin, in its Ser3 dephosphorylated form, accelerates actin filament turnover in cells. We report here the role of cofilin in platelet actin assembly. Cofilin is primarily phosphorylated in the resting platelet as evidenced by a specific antibody directed against its Ser3 phosphorylated form. After stimulation with thrombin under nonstirring conditions, cofilin is reversibly dephosphorylated and transiently incorporates into the actin cytoskeleton. Its dephosphorylation is maximal 1-2 min after platelet stimulation, shortly after the peak of actin assembly occurs. Cofilin rephosphorylation begins 2 min after activation and exceeds resting levels by 5-10 min. Cofilin is dephosphorylated with identical kinetics but fails to become rephosphorylated when platelets are stimulated under stirring conditions. Cofilin is normally rephosphorylated when platelets are stimulated in the presence of Arg-Gly-Asp-Ser (RGDS) peptide or wortmannin to block alpha(IIb)beta3 cross-linking and signaling or in platelets isolated from a patient with Glanzmann thrombasthenia, which express only 2-3% of normal alpha(IIb)beta3 levels. Furthermore, actin assembly and Arp2/3 complex incorporation in the platelet actin cytoskeleton are decreased when alpha(IIb)beta3 is engaged. Our results suggest that cofilin is essential for actin dynamics mediated by outside-in signals in activated platelets.

Regulation of LIM-kinase 1 and cofilin in thrombin-stimulated platelets

“…14,40 However, in TRAP-stimulated platelets no decrease of cofilin phosphorylation, only an increase 3 to 5 minutes after activation was found. 41 In contrast to our results, the study of Falet et al 40 For personal use only.…”

Down-regulation of uPAR and Cathepsin B retards cofilin dephosphorylation

“…Previous studies have suggested the importance of cofilin in actin dynamics (19) and that the dephosphorylation of cofilin is initiated through extracellular signaling mediated by integrins. Our results demonstrated that the simultaneous down-regulation of uPAR and cathepsin B not only hinders the activation of cofilin but also down-regulates levels of the · V ß 3 integrin heterodimer as seen from FACS analysis and Western blotting.…”

Wiskott-Aldrich Syndrome Protein (WASp) Controls the Delivery of Platelet Transforming Growth Factor-β1

“…In either case, the signals that regulate ␣-granule secretion are likely integrated with the actin cytoskeleton, which is extensively remodeled upon platelet activation (7). In platelets, actin assembly and disassembly are tightly orchestrated by a number of accessory proteins including vinculin (8), cortactin (9), filamin A (10), talin (11), gelsolin (12), cofilin (13), ARP2/3 complex (14), and WAVE (15).…”