Document Detail


Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein.
MedLine Citation:
PMID:  16489009     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Histidine-rich glycoprotein (HRGP) is an abundant heparin-binding plasma protein that efficiently arrests growth and vascularization of mouse tumor models. We have shown that the antiangiogenic effect of HRGP is dependent on its histidine/proline-rich domain, which needs to be released from the mother protein to exert its effects. Here we identify a 35-amino-acid peptide, HRGP330, derived from the histidine/proline-rich domain as endowed with antiangiogenic properties in vitro and in vivo. The mechanism of action of HRGP330 involves subversion of focal adhesion function by disruption of integrin-linked kinase (ILK) and focal adhesion kinase (FAK) functions, inhibition of vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of the FAK substrate alpha-actinin, and, as a consequence, an arrest in endothelial cell motility. The disturbed focal adhesion function is reflected in the ability of HRGP as well as of HRGP330 to prevent endothelial cell adhesion to vitronectin in a manner involving alpha(v)beta3 integrin. In conclusion, HRGP330, which we define as the minimal antiangiogenic domain of HRGP, exerts its effects through signal transduction targeting focal adhesions, thereby interrupting VEGF-induced endothelial cell motility.
Authors:
Johan Dixelius; Anna-Karin Olsson; Asa Thulin; Chunsik Lee; Irja Johansson; Lena Claesson-Welsh
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  66     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-20     Completed Date:  2006-04-13     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2089-97     Citation Subset:  IM    
Affiliation:
Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Actinin / metabolism
Amino Acid Sequence
Animals
Cattle
Cell Movement / drug effects,  physiology
Endothelial Cells / cytology,  drug effects*
Focal Adhesion Protein-Tyrosine Kinases / metabolism
Integrin alphaVbeta3 / metabolism
Molecular Sequence Data
Neovascularization, Physiologic / drug effects*
Paxillin / antagonists & inhibitors,  biosynthesis
Peptide Fragments / chemistry,  pharmacology*
Phosphorylation / drug effects
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases / metabolism
Proteins / chemistry,  pharmacology*
Vascular Endothelial Growth Factor A / antagonists & inhibitors,  metabolism,  pharmacology
Vascular Endothelial Growth Factor Receptor-2 / metabolism
Chemical
Reg. No./Substance:
0/Integrin alphaVbeta3; 0/Paxillin; 0/Peptide Fragments; 0/Proteins; 0/Vascular Endothelial Growth Factor A; 0/histidine-rich proteins; 11003-00-2/Actinin; EC 2.7.1.-/integrin-linked kinase; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2; EC 2.7.10.2/Focal Adhesion Protein-Tyrosine Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases

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


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