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PMID:16489009

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Citation

Dixelius, J, Olsson, AK, Thulin, A, Lee, C, Johansson, I and Claesson-Welsh, L (2006) Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein. Cancer Res. 66:2089-97

Abstract

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.

Links

PubMed Online version:10.1158/0008-5472.CAN-05-2217

Keywords

Actinin/metabolism; Amino Acid Sequence; Animals; Cattle; Cell Movement/drug effects; Cell Movement/physiology; Endothelial Cells/cytology; Endothelial Cells/drug effects; Focal Adhesion Protein-Tyrosine Kinases/metabolism; Integrin alphaVbeta3/metabolism; Molecular Sequence Data; Neovascularization, Physiologic/drug effects; Paxillin/antagonists & inhibitors; Paxillin/biosynthesis; Peptide Fragments/chemistry; Peptide Fragments/pharmacology; Phosphorylation/drug effects; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases/metabolism; Proteins/chemistry; Proteins/pharmacology; Vascular Endothelial Growth Factor A/antagonists & inhibitors; Vascular Endothelial Growth Factor A/metabolism; Vascular Endothelial Growth Factor A/pharmacology; Vascular Endothelial Growth Factor Receptor-2/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:HRG

involved_in

GO:0043254: regulation of protein-containing complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0031334: positive regulation of protein-containing complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0001938: positive regulation of endothelial cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0031334: positive regulation of protein complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0050731: positive regulation of peptidyl-tyrosine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:VEGFA

involved_in

GO:0051894: positive regulation of focal adhesion assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HRG

involved_in

GO:0050730: regulation of peptidyl-tyrosine phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HRG

involved_in

GO:0010593: negative regulation of lamellipodium assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HRG

involved_in

GO:0016525: negative regulation of angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HRG

involved_in

GO:0032956: regulation of actin cytoskeleton organization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HRG

involved_in

GO:1900747: negative regulation of vascular endothelial growth factor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HRG

involved_in

GO:0033629: negative regulation of cell adhesion mediated by integrin

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HRG

involved_in

GO:0043254: regulation of protein complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HRG

involved_in

GO:2001027: negative regulation of endothelial cell chemotaxis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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