Signal transduction in endothelial cells by the angiogenesis inhibitor histidine-rich glycoprotein targets focal adhesions

Journal Article · Tue Aug 01 00:00:00 EDT 2006 · Experimental Cell Research

DOI:https://doi.org/10.1016/j.yexcr.2006.04.022· OSTI ID:20858010

Lee, Chunsik ^[1]; Dixelius, Johan ^[1]; Thulin, Asa ^[1]; Kawamura, Harukiyo ^[1]; Claesson-Welsh, Lena ^[1]; Olsson, Anna-Karin ^[1]

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1. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjoelds vaeg 20, SE-751 85 Uppsala (Sweden)

Histidine-rich glycoprotein (HRGP) is an abundant heparin-binding plasma protein. We have shown that a fragment released from the central histidine/proline-rich (His/Pro-rich) domain of HRGP blocks endothelial cell migration in vitro and vascularization and growth of murine fibrosarcoma in vivo. The minimal active HRGP domain exerting the anti-angiogenic effect was recently narrowed down to a 35 amino acid peptide, HRGP330, derived from the His/Pro-rich domain of HRGP. By use of a signal transduction antibody array representing 400 different signal transduction molecules, we now show that HRGP and the synthetic peptide HRGP330 specifically induce tyrosine phosphorylation of focal adhesion kinase and its downstream substrate paxillin in endothelial cells. HRGP/HRGP330 treatment of endothelial cells induced disruption of actin stress fibers, a process reversed by treatment of cells with the FAK inhibitor geldanamycin. In addition, VEGF-mediated endothelial cell tubular morphogenesis in a three-dimensional collagen matrix was inhibited by HRGP and HRGP330. In contrast, VEGF-induced proliferation was not affected by HRGP or HRGP330, demonstrating the central role of cell migration during tube formation. In conclusion, our data show that HRGP targets focal adhesions in endothelial cells, thereby disrupting the cytoskeletal organization and the ability of endothelial cells to assemble into vessel structures.

• OSTI ID: 20858010
• Journal Information: Experimental Cell Research, Vol. 312, Issue 13; Other Information: DOI: 10.1016/j.yexcr.2006.04.022; PII: S0014-4827(06)00163-7; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACTIN
ANTIBODIES
BIOLOGICAL STRESS
COLLAGEN
FIBERS
GLYCOPROTEINS
HEPARIN
HISTIDINE
IN VITRO
IN VIVO
MORPHOGENESIS
PEPTIDES
PHOSPHORYLATION
PROLINE
SUBSTRATES
TYROSINE