Document Detail


Regulation of transforming growth factor-beta activation by discrete sequences of thrombospondin 1.
MedLine Citation:
PMID:  7706271     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Transforming growth factor-beta (TGF-beta) is a potent growth regulatory protein secreted by virtually all cells in a latent form. A major mechanism of regulating TGF-beta activity occurs through factors that control the processing of the latent to the biologically active form of the molecule. We have shown previously that thrombospondin 1 (TSP1), a platelet alpha-granule and extracellular matrix protein, activates latent TGF-beta via a protease- and cell-independent mechanism and have localized the TGF-beta binding/activation region to the type 1 repeats of platelet TSP1. We now report that recombinant human TSP1, but not recombinant mouse TSP2, activates latent TGF-beta. Activation was further localized to the unique sequence RFK found between the first and the second type 1 repeats of TSP1 (amino acids 412-415) by the use of synthetic peptides. A peptide with the corresponding sequence in TSP2, RIR, was inactive. In addition, a hexapeptide GGWSHW, based on a sequence present in the type 1 repeats of both TSP1 and TSP2, inhibited the activation of latent TGF-beta by TSP1. This peptide bound to 125I-active TGF-beta and inhibited interactions of TSP1 with latent TGF-beta. TSP2 also inhibited activation of latent TGF-beta by TSP1, presumably by competitively binding to TGF-beta through the WSHW sequence. These studies show that activation of latent TGF-beta is mediated by two sequences present in the type 1 repeats of TSP1, a sequence (GGWSHW) that binds active TGF-beta and potentially orients the TSP molecule and a second sequence (RFK) that activates latent TGF-beta. Peptides based on these sites have potential therapeutic applications for modulation of TGF-beta activation.
Authors:
S Schultz-Cherry; H Chen; D F Mosher; T M Misenheimer; H C Krutzsch; D D Roberts; J E Murphy-Ullrich
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  270     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1995 Mar 
Date Detail:
Created Date:  1995-05-10     Completed Date:  1995-05-10     Revised Date:  2013-04-24    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  7304-10     Citation Subset:  IM    
Affiliation:
Department of Pathology, University of Alabama at Birmingham 35294-0019, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Binding Sites
Cell Adhesion / drug effects*
Cell Adhesion Molecules / pharmacology
Cell Line
Enzyme-Linked Immunosorbent Assay
Heparin / pharmacology
Humans
Kinetics
Membrane Glycoproteins / metabolism,  pharmacology*
Mice
Molecular Sequence Data
Oligopeptides / chemical synthesis,  pharmacology
Peptide Fragments / pharmacology
Peptides / chemical synthesis,  pharmacology
Rats
Recombinant Proteins / metabolism,  pharmacology
Spodoptera
Structure-Activity Relationship
Thrombospondins
Transfection
Transforming Growth Factor beta / metabolism*,  pharmacology*
Grant Support
ID/Acronym/Agency:
HL08640/HL/NHLBI NIH HHS; HL49111/HL/NHLBI NIH HHS; HL50061/HL/NHLBI NIH HHS; R01 HL050061/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cell Adhesion Molecules; 0/Membrane Glycoproteins; 0/Oligopeptides; 0/Peptide Fragments; 0/Peptides; 0/Recombinant Proteins; 0/Thrombospondins; 0/Transforming Growth Factor beta; 9005-49-6/Heparin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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