Assembly of multimeric von Willebrand factor directs sorting of P-selectin

被引:30
作者
Hop, C
Guilliatt, A
Daly, M
de Leeuw, HP
Brinkman, HJM
Peake, IR
van Mourik, JA
Pannekoek, H
机构
[1] Univ Amsterdam, Acad Med Ctr, Dept Biochem K1 159, NL-1105 AZ Amsterdam, Netherlands
[2] Univ Sheffield, Dept Med & Pharmacol, Mol Genet Sect, Sheffield, S Yorkshire, England
[3] Sanquin Blood Supply Bdn, CLB, Dept Blood Coagulat, Amsterdam, Netherlands
关键词
von Willebrand factor; P-selectin; Weibel-Palade bodies; protein sorting;
D O I
10.1161/01.ATV.20.7.1763
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We designed a model system to study the role of von Willebrand factor (vWF) in the sorting of P-selectin and the biogenesis of Weibel-Palade body (WPB)-like organelles. For that purpose, a human epithelial cell line (T24) that synthesizes P-selectin mRNA, but which is devoid of vWF mRNA synthesis and storage organelles, was transfected with full-length vWF cDNA or a deletion mutant thereof. Stable transfectants of T24 with full-length vWF cDNA revealed the generation of WPB-like organelles as demonstrated by colocalization of vWF and P-selectin with double-labeling immunofluorescence. In contrast, T24 cells transfected with vWF delD'D3 cDNA, encoding a mutant that is unable to form vWF multimers, displayed only perinuclear vWF staining, whereas no indication was found for the presence of WPB-like organelles. The contents of the organelles in full-length vWF cDNA-transfected T24 cells were released on activation of the protein kinase C pathway, similar to the situation with genuine endothelial cells. The expression of vWF did not affect the biosynthesis of P-selectin, as deduced from the observation that untransfected and vWF cDNA-transfected T24 cells contained the same amount of P-selectin mRNA, We propose that the biosynthesis of multimeric vWF directs the generation of WPB-like organelles, as evidenced by the sequestering and anchoring of P-selectin into these storage granules.
引用
收藏
页码:1763 / 1768
页数:6
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