Document Detail


Cell cholesterol modulates metalloproteinase-dependent shedding of low-density lipoprotein receptor-related protein-1 (LRP-1) and clearance function.
MedLine Citation:
PMID:  21518850     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Low-density lipoprotein receptor-related protein-1 (LRP-1) is a plasma membrane scavenger and signaling receptor, composed of a large ligand-binding subunit (515-kDa α-chain) linked to a shorter transmembrane subunit (85-kDa β-chain). LRP-1 cell-surface level and function are controlled by proteolytic shedding of its ectodomain. Here, we identified ectodomain sheddases in human HT1080 cells and demonstrated regulation of the cleavage by cholesterol by comparing the classical fibroblastoid type with a spontaneous epithelioid variant, enriched ∼ 2-fold in cholesterol. Two membrane-associated metalloproteinases were involved in LRP-1 shedding: a disintegrin and metalloproteinase-12 (ADAM-12) and membrane-type 1 matrix metalloproteinase (MT1-MMP). Although both variants expressed similar levels of LRP-1, ADAM-12, MT1-MMP, and specific tissue inhibitor of metalloproteinases-2 (TIMP-2), LRP-1 shedding from epithelioid cells was ∼4-fold lower than from fibroblastoid cells. Release of the ectodomain was triggered by cholesterol depletion in epithelioid cells and impaired by cholesterol overload in fibroblastoid cells. Modulation of LRP-1 shedding on clearance was reflected by accumulation of gelatinases (MMP-2 and MMP-9) in the medium. We conclude that cholesterol exerts an important control on LRP-1 levels and function at the plasma membrane by modulating shedding of its ectodomain, and therefore represents a novel regulator of extracellular proteolytic activities.
Authors:
Charlotte Selvais; Ludovic D'Auria; Donatienne Tyteca; Gwenn Perrot; Pascale Lemoine; Linda Troeberg; Stéphane Dedieu; Agnès Noël; Hideaki Nagase; Patrick Henriet; Pierre J Courtoy; Etienne Marbaix; Hervé Emonard
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-04-25
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  25     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-02     Completed Date:  2011-10-14     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2770-81     Citation Subset:  IM    
Affiliation:
Cell Biology Laboratory, de Duve Institute, UCL-75.41, 75 avenue Hippocrate, B-1200 Bruxelles, Belgium.
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MeSH Terms
Descriptor/Qualifier:
ADAM Proteins / antagonists & inhibitors,  genetics,  metabolism
Antigens, CD / chemistry,  metabolism*
Base Sequence
Cell Line, Tumor
Cell Membrane / metabolism
Cholesterol / metabolism*
Epithelioid Cells / metabolism
Fibroblasts / metabolism
Humans
Low Density Lipoprotein Receptor-Related Protein-1 / chemistry,  metabolism*
Matrix Metalloproteinase 14 / metabolism
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 9 / metabolism
Membrane Proteins / antagonists & inhibitors,  genetics,  metabolism
Metalloproteases / metabolism*
Protein Structure, Tertiary
RNA, Small Interfering / genetics
Signal Transduction
Grant Support
ID/Acronym/Agency:
AR40994/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/LRP1 protein, human; 0/Low Density Lipoprotein Receptor-Related Protein-1; 0/Membrane Proteins; 0/RNA, Small Interfering; 57-88-5/Cholesterol; EC 3.4.-/Metalloproteases; EC 3.4.24.-/ADAM 12 protein; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.24/MMP2 protein, human; EC 3.4.24.24/Matrix Metalloproteinase 2; EC 3.4.24.35/Matrix Metalloproteinase 9; EC 3.4.24.80/MMP14 protein, human; EC 3.4.24.80/Matrix Metalloproteinase 14
Comments/Corrections

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