Home LiteratureArticle Details
PMID: 15257287 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Rab3D and annexin A2 play a role in regulated secretion of vWF, but not tPA, from endothelial cells.

The EMBO journal ·Vol. 23 ·No. 15 ·2004-08-04 ·Pages 2982-92

Knop M, Aareskjold E, Bode G, Gerke V

Abstract

von-Willebrand factor (vWF) and tissue-type plasminogen activator (tPA) are products of endothelial cells acutely released into the vasculature following cell activation. Both factors are secreted after intraendothelial Ca2+ mobilization, but exhibit opposing physiological effects with vWF inducing coagulation and tPA triggering fibrinolysis. To identify components that could regulate differentially the release of pro- and antithrombogenic factors, we analyzed the contribution of Rab3D and the annexin A2/S100A10 complex, proteins implicated in exocytotic events in other systems. We show that mutant Rab3D proteins interfere with the formation of bona fide Weibel-Palade bodies (WPbs), the principal storage granules of multimeric vWF, and consequently the acute, histamine-induced release of vWF. In contrast, neither appearance nor exocytosis of tPA storage granules is affected. siRNA-mediated downregulation of annexin A2/S100A10 and disruption of the complex by microinjection of peptide competitors result in a marked reduction in vWF but not tPA secretion, without affecting the appearance of WPbs. This indicates that distinct mechanisms underlie the acute secretion of vWF and tPA, enabling endothelial cells to fine-regulate the release of thrombogenic and fibrinolytic factors.

MeSH Terms
Annexin A2/metabolism Cells, Cultured Down-Regulation Endocytosis Endothelial Cells/drug effects,metabolism Histamine/pharmacology Humans Mutation/genetics Protein Binding RNA, Small Interfering/genetics S100 Proteins/metabolism Time Factors Tissue Plasminogen Activator/metabolism Weibel-Palade Bodies/metabolism rab3 GTP-Binding Proteins/genetics,metabolism von Willebrand Factor/metabolism
Chemicals
Annexin A2 RNA, Small Interfering S100 Proteins S100 calcium binding protein A10 von Willebrand Factor Histamine Tissue Plasminogen Activator RAB3D protein, human rab3 GTP-Binding Proteins
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Knop Markus
Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Münster, Münster, Germany.
Aareskjold Elin
Bode Günther
Gerke Volker
References (37)
37 references, click to expand
  1. Purine nucleotides induce regulated secretion of von Willebrand factor: involvement of cytosolic Ca2+ and cyclic adenosine monophosphate-dependent signaling in endothelial exocytosis.
    Blood. 1998 Jan 1;91(1):118-27 PMID: 9414275
  2. Annexins: from structure to function.
    Physiol Rev. 2002 Apr;82(2):331-71 PMID: 11917092
  3. The annexin II-p11 complex is involved in regulated exocytosis in bovine pulmonary artery endothelial cells.
    J Biol Chem. 1998 Jul 31;273(31):19679-84 PMID: 9677396
  4. Dominant negative Rab3D inhibits amylase release from mouse pancreatic acini.
    J Biol Chem. 2002 May 17;277(20):18002-9 PMID: 11875077
  5. Selective and signal-dependent recruitment of membrane proteins to secretory granules formed by heterologously expressed von Willebrand factor.
    Mol Biol Cell. 2002 May;13(5):1582-93 PMID: 12006654
  6. Rab3D is not required for exocrine exocytosis but for maintenance of normally sized secretory granules.
    Mol Cell Biol. 2002 Sep;22(18):6487-97 PMID: 12192047
  7. Localization versus function of Rab3 proteins. Evidence for a common regulatory role in controlling fusion.
    J Biol Chem. 2002 Oct 25;277(43):40919-29 PMID: 12167638
  8. Differential exocytosis from human endothelial cells evoked by high intracellular Ca(2+) concentration.
    J Physiol. 2002 Nov 1;544(Pt 3):741-55 PMID: 12411520
  9. Ca2+ -regulated secretion of tissue-type plasminogen activator and von Willebrand factor in human endothelial cells.
    Biochim Biophys Acta. 2002 Nov 4;1600(1-2):162-7 PMID: 12445472
  10. Secretory granules are recaptured largely intact after stimulated exocytosis in cultured endocrine cells.
    Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2070-5 PMID: 12538853
  11. Differential actions of PAR2 and PAR1 in stimulating human endothelial cell exocytosis and permeability: the role of Rho-GTPases.
    Circ Res. 2003 Feb 21;92(3):272-8 PMID: 12595338
  12. Endothelial cell functions.
    J Cell Physiol. 2003 Sep;196(3):430-43 PMID: 12891700
  13. Weibel-Palade bodies recruit Rab27 by a content-driven, maturation-dependent mechanism that is independent of cell type.
    J Cell Sci. 2003 Oct 1;116(Pt 19):3939-48 PMID: 12928333
  14. The annexin 2/S100A10 complex controls the distribution of transferrin receptor-containing recycling endosomes.
    Mol Biol Cell. 2003 Dec;14(12):4896-908 PMID: 13679511
  15. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria.
    J Clin Invest. 1973 Nov;52(11):2745-56 PMID: 4355998
  16. p36, the major cytoplasmic substrate of src tyrosine protein kinase, binds to its p11 regulatory subunit via a short amino-terminal amphiphatic helix.
    EMBO J. 1988 Aug;7(8):2435-42 PMID: 2973411
  17. A role for calpactin in calcium-dependent exocytosis in adrenal chromaffin cells.
    Nature. 1989 Jul 27;340(6231):313-5 PMID: 2526299
  18. The participation of annexin II (calpactin I) in calcium-evoked exocytosis requires protein kinase C.
    J Cell Biol. 1991 Sep;114(6):1135-47 PMID: 1832677
  19. The Weibel-Palade body: the storage granule for von Willebrand factor and P-selectin.
    Thromb Haemost. 1993 Jul 1;70(1):105-10 PMID: 7694385
  20. Prolonged peak elevations in cytoplasmic free calcium ions, derived from intracellular stores, correlate with the extent of thrombin-stimulated exocytosis in single human umbilical vein endothelial cells.
    J Cell Physiol. 1994 Sep;160(3):545-54 PMID: 7521337
  21. Regulation of endothelial cell t-PA synthesis and release.
    Int J Hematol. 1994 Jun;59(4):233-55 PMID: 8086618
  22. Thrombin induces the redistribution and acute release of tissue factor pathway inhibitor from specific granules within human endothelial cells in culture.
    Arterioscler Thromb Vasc Biol. 1995 Nov;15(11):2055-62 PMID: 7583589
  23. Modification of annexin II expression in PC12 cell lines does not affect Ca(2+)-dependent exocytosis.
    Mol Biol Cell. 1997 Mar;8(3):431-42 PMID: 9188096
  24. An endothelial storage granule for tissue-type plasminogen activator.
    J Cell Biol. 1997 Oct 6;139(1):245-56 PMID: 9314543
  25. Thrombosis and atherosclerosis.
    Curr Opin Lipidol. 1997 Oct;8(5):320-8 PMID: 9335957
  26. Membrane capacitance changes induced by thrombin and calcium in single endothelial cells cultured from human umbilical vein.
    J Physiol. 1998 Dec 15;513 ( Pt 3):845-55 PMID: 9824722
  27. Storage of tissue-type plasminogen activator in Weibel-Palade bodies of human endothelial cells.
    Arterioscler Thromb Vasc Biol. 1999 Jul;19(7):1796-803 PMID: 10397700
  28. Targeting of a heterologous protein to a regulated secretion pathway in cultured endothelial cells.
    Blood. 1999 Oct 15;94(8):2696-703 PMID: 10515873
  29. NEW CYTOPLASMIC COMPONENTS IN ARTERIAL ENDOTHELIA.
    J Cell Biol. 1964 Oct;23:101-12 PMID: 14228505
  30. Rab3A and Rab3D control the total granule number and the fraction of granules docked at the plasma membrane in PC12 cells.
    Traffic. 2000 Dec;1(12):976-86 PMID: 11208087
  31. Kiss and run mechanism in exocytosis.
    J Membr Biol. 2001 May 15;181(2):67-76 PMID: 11420594
  32. Annexin 2 has an essential role in actin-based macropinocytic rocketing.
    Curr Biol. 2001 Jul 24;11(14):1136-41 PMID: 11509239
  33. Regulated von Willebrand factor secretion is associated with agonist-specific patterns of cytoskeletal remodeling in cultured endothelial cells.
    Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):883-91 PMID: 10712417
  34. Ion channels and their functional role in vascular endothelium.
    Physiol Rev. 2001 Oct;81(4):1415-59 PMID: 11581493
  35. Regulated secretion in endothelial cells: biology and clinical implications.
    Thromb Haemost. 2001 Nov;86(5):1148-55 PMID: 11816699
  36. Cell-surface attachment of pedestal-forming enteropathogenic E. coli induces a clustering of raft components and a recruitment of annexin 2.
    J Cell Sci. 2002 Jan 1;115(Pt 1):91-8 PMID: 11801727
  37. Expression of Rab3D N135I inhibits regulated secretion of ACTH in AtT-20 cells.
    J Cell Biol. 1998 Jan 26;140(2):305-13 PMID: 9442106
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7600319
Published
2004-08-04
Epub
2004-00-15
Pages
2982-92
Language
English
Region
England
NLM ID
8208664
PMCID
PMC514934
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.emboj.7600319 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2