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Minimal Active Domain and Mechanism of Action of the Angiogenesis Inhibitor Histidine-Rich Glycoprotein

Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden

Requests for reprints: Lena Claesson-Welsh, Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Dag Hammarskjölds väg 20, SE-751 85 Uppsala, Sweden. E-mail: Lena.Welsh{at}genpat.uu.se.

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 -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 _vß₃ 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. (Cancer Res 2006; 66(4): 2089-97)

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