Research article summary (published 10 Oct 2009):

Urokinase-receptor-mediated phenotypic changes in vascular smooth muscle cells require the involvement of membrane rafts.

Full Abstract

The cholesterol-enriched membrane microdomains lipid rafts play a key role in cell activation by recruiting and excluding specific signalling components of cell-surface receptors upon receptor engagement. Our previous studies have demonstrated that the GPI (glycosylphosphatidylinositol)-linked uPAR [uPA (urokinase-type plasminogen activator) receptor], which can be found in lipid rafts and in non-raft fractions, can mediate the differentiation of VSMCs (vascular smooth muscle cells) towards a pathophysiological de-differentiated phenotype. However, the mechanism by which uPAR and its ligand uPA regulate VSMC phenotypic changes is not known. In the present study, we provide evidence that the molecular machinery of uPAR-mediated VSMC differentiation employs lipid rafts. We show that the disruption of rafts in VSMCs by membrane cholesterol depletion using MCD (methyl-beta-cyclodextrin) or filipin leads to the up-regulation of uPAR and cell de-differentiation. uPAR silencing by means of interfering RNA resulted in an increased expression of contractile proteins. Consequently, disruption of lipid rafts impaired the expression of these proteins and transcriptional activity of related genes. We provide evidence that this effect was mediated by uPAR. Similar effects were observed in VSMCs isolated from Cav1Z(-/-) (caveolin-1-deficient) mice. Despite the level of uPAR being significantly higher after the disruption of the rafts, uPA/uPAR-dependent cell migration was impaired. However, caveolin-1 deficiency impaired only uPAR-dependent cell proliferation, whereas cell migration was strongly up-regulated in these cells. Our results provide evidence that rafts are required in the regulation of uPAR-mediated VSMC phenotypic modulations. These findings suggest further that, in the context of uPA/uPAR-dependent processes, caveolae-associated and non-associated rafts represent different signalling membrane domains.

Author information

Author/s: Kiyan, Julia (J); Smith, Graham (G); Haller, Hermann (H); Dumler, Inna (I);

Affiliation: Hannover Medical School, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany. kiian.ioulia(-atsign-)mh-hannover.de

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: The Biochemical journal (Biochem J), published in England. (Language: eng)

Reference: 2009-Nov; vol 423 (issue 3) : pp 343-51

Dates: Created 2009/10/07; Completed 2009/11/03;

PMID: 19691446, status: MEDLINE (last retrieval date: 11/3/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Anti-Bacterial Agents - pharmacology Caveolin 1 - genetics; metabolism Cell Dedifferentiation - drug effects; physiology Cell Differentiation - drug effects; physiology Cell Movement - drug effects; physiology Cells, Cultured Filipin - pharmacology Gene Expression Regulation - drug effects; physiology Gene Silencing

Humans Membrane Microdomains - genetics; metabolism Mice Mice, Knockout Muscle, Smooth, Vascular - cytology; metabolism Myocytes, Smooth Muscle - cytology; metabolism Receptors, Urokinase Plasminogen Activator - genetics; metabolism Transcription, Genetic - drug effects; physiology Urokinase-Type Plasminogen Activator - genetics; metabolism beta-Cyclodextrins - pharmacology

Associated Chemicals: Anti-Bacterial Agents (0) ; Caveolin 1 (0) ; PLAUR protein, human (0) ; Plaur protein, mouse (0) ; Receptors, Urokinase Plasminogen Activator (0) ; beta-Cyclodextrins (0) ; methyl-beta-cyclodextrin (0) ; Filipin (480-49-9) ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73)

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