Document Detail

MT1-MMP promotes vascular smooth muscle dedifferentiation through LRP1 processing.
MedLine Citation:
PMID:  19066283     Owner:  NLM     Status:  MEDLINE    
At sites of vessel-wall injury, vascular smooth muscle cells (VSMCs) can dedifferentiate to express an invasive and proliferative phenotype, which contributes to the development of neointimal lesions and vascular disorders. Herein, we demonstrate that the loss of the VSMC differentiated phenotype, as the repression of contractile-protein expression, is correlated with a dramatic upregulation of the membrane-anchored matrix metalloproteinase MT1-MMP (also known as MMP14 and membrane-type 1 matrix metalloproteinase). Matrix metalloproteinase (MMP) inhibitors or MT1-MMP deficiency led to attenuated VSMC dedifferentiation, whereas the phenotypic switch was re-engaged following the restoration of MT1-MMP activity in MT1-MMP(-/-) cells. MT1-MMP-dependent dedifferentiation was mediated by the PDGF-BB-PDGFRbeta pathway in parallel with the proteolytic processing of the multifunctional LDL receptor-related protein LRP1 and the dynamic internalization of a PDGFRbeta-beta3-integrin-MT1-MMP-LRP1 multi-component complex. Importantly, LRP1 silencing allowed the PDGF-BB-induced dedifferentiation program to proceed in the absence of MT1-MMP activity, supporting the role of unprocessed LRP1 as a gatekeeper of VSMC differentiation. Hence, MT1-MMP and LRP1 serve as a new effector-target-molecule axis that controls the PDGF-BB-PDGFRbeta-dependent VSMC phenotype and function.
Kaisa Lehti; Nina F Rose; Sara Valavaara; Stephen J Weiss; Jorma Keski-Oja
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-12-09
Journal Detail:
Title:  Journal of cell science     Volume:  122     ISSN:  0021-9533     ISO Abbreviation:  J. Cell. Sci.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2008-12-18     Completed Date:  2009-03-16     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0052457     Medline TA:  J Cell Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  126-35     Citation Subset:  IM    
Department of Pathology and Virology, Haartman Institute, University of Helsinki, FIN-00014 Helsinki, Finland.
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MeSH Terms
Caveolins / metabolism
Cell Dedifferentiation / physiology*
Cells, Cultured
Contractile Proteins / genetics,  metabolism
Gene Knockdown Techniques
Matrix Metalloproteinase 14 / genetics,  metabolism*
Mice, Knockout
Muscle, Smooth, Vascular* / cytology,  physiology
Myocytes, Smooth Muscle / cytology,  physiology*
Platelet-Derived Growth Factor / genetics,  metabolism
Receptor, Platelet-Derived Growth Factor beta / genetics,  metabolism
Receptors, LDL / genetics,  metabolism*
Tumor Suppressor Proteins / genetics,  metabolism*
Reg. No./Substance:
0/Caveolins; 0/Contractile Proteins; 0/Lrp1 protein, mouse; 0/Platelet-Derived Growth Factor; 0/Receptors, LDL; 0/Tumor Suppressor Proteins; 0/platelet-derived growth factor BB; EC, Platelet-Derived Growth Factor beta; EC Metalloproteinase 14

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