Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein
2006 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 4, 2089-97 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2006. Vol. 66, no 4, 2089-97 p.
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, Research Support; Non-U.S. Gov't, Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism/pharmacology, Vascular Endothelial Growth Factor Receptor-2/metabolism
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-80197DOI: 10.1158/0008-5472.CAN-05-2217PubMedID: 16489009OAI: oai:DiVA.org:uu-80197DiVA: diva2:108111