Document Detail

beta(3)A-integrin downregulates the urokinase-type plasminogen activator receptor (u-PAR) through a PEA3/ets transcriptional silencing element in the u-PAR promoter.
MedLine Citation:
PMID:  11238946     Owner:  NLM     Status:  MEDLINE    
Migration of cells requires interactions with the extracellular matrix mediated, in part, by integrins, proteases, and their receptors. Previous studies have shown that beta(3)-integrin interacts with the urokinase-type plasminogen activator receptor (u-PAR) at the cell surface. Since integrins mediate signaling into the cell, the current study was undertaken to determine if in addition beta(3)-integrin regulates u-PAR expression. Overexpression of beta(3)-integrin in CHO cells, which are avid expressers of the receptor, downregulated u-PAR protein and mRNA expression. The u-PAR promoter (-1,469 bp) that is normally constitutively active in CHO cells was downregulated by induced beta(3)-integrin expression. A region between -398 and -197 bp of the u-PAR promoter was critical for beta(3)-integrin-induced downregulation of u-PAR promoter activity. Deletion of the PEA3/ets motif at -248 bp substantially impaired the ability of beta(3)-integrin to downregulate the u-PAR promoter, suggesting that the PEA3/ets site acts as a silencing element. An expression vector encoding the transcription factor PEA3 caused inhibition of the wild-type but not the PEA3/ets-deleted u-PAR promoter. The PEA3/ets site bound nuclear factors from CHO cells specifically, but binding was enhanced when beta(3)-integrin was overexpressed. A PEA3 antibody inhibited DNA-protein complex formation, indicating the presence of PEA3. Downregulation of the u-PAR promoter was achieved by the beta(3)A-integrin isoform but not by other beta(3)-integrin isoforms and required the cytoplasmic membrane NITY(759) motif. Moreover, overexpression of the short but not the long isoform of the beta(3)-integrin adapter protein beta(3)-endonexin blocked u-PAR promoter activity through the PEA3/ets binding site. Thus, besides the physical interaction of beta(3)-integrin and u-PAR at the cell surface, beta(3) signaling is implicated in the regulation of u-PAR gene transcription, suggesting a mutual regulation of adhesion and proteolysis receptors.
S Hapke; M Gawaz; K Dehne; J Köhler; J F Marshall; H Graeff; M Schmitt; U Reuning; E Lengyel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular and cellular biology     Volume:  21     ISSN:  0270-7306     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2001 Mar 
Date Detail:
Created Date:  2001-03-12     Completed Date:  2001-04-19     Revised Date:  2013-04-17    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2118-32     Citation Subset:  IM    
Department of Obstetrics and Gynecology, Deutsches Herzzentrum, Technische Universität München, Klinikum rechts der Isar, D-81675 Munich, Germany.
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MeSH Terms
Amino Acid Sequence
Antigens, CD / genetics,  metabolism*
Base Sequence
Binding Sites
CHO Cells
Cytoplasm / metabolism
Gene Expression Regulation
Integrin beta3
Molecular Sequence Data
Nuclear Proteins
Platelet Membrane Glycoproteins / genetics,  metabolism*
Promoter Regions, Genetic
Protein Structure, Tertiary
Proteins / genetics,  metabolism
Receptors, Cell Surface / genetics*,  metabolism
Receptors, Urokinase Plasminogen Activator
Recombinant Proteins / genetics,  metabolism
Regulatory Sequences, Nucleic Acid*
Transcription, Genetic*
Reg. No./Substance:
0/Antigens, CD; 0/ITGB3BP protein, human; 0/Integrin beta3; 0/Nuclear Proteins; 0/Platelet Membrane Glycoproteins; 0/Proteins; 0/Receptors, Cell Surface; 0/Receptors, Urokinase Plasminogen Activator; 0/Recombinant Proteins

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