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J. Biol. Chem., Vol. 279, Issue 19, 20178-20185, May 7, 2004

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An Endostatin-derived Peptide Interacts with Integrins and Regulates Actin Cytoskeleton and Migration of Endothelial Cells^*

Sara A. Wickström, Kari Alitalo¶, and Jorma Keski-Oja||

From the Departments of Pathology and Virology, Haartman Institute, and the ^¶Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, University of Helsinki, Biomedicum Helsinki and Helsinki University Hospital, FIN-00014 Helsinki, Finland

Endostatin, the C-terminal fragment of collagen XVIII, is a potent inhibitor of angiogenesis and endothelial cell migration. To define its critical cell interaction domains we used endostatin-derived synthetic peptides containing surface-exposed sequences. We observed that, when immobilized, an arginine-rich peptide of 11 amino acids from its N terminus efficiently promoted endothelial cell adhesion through ₁ integrin- and heparin-dependent mechanisms. In addition, the peptide induced the formation of membrane ruffles and focal contacts. In the soluble form, the peptide inhibited basic fibroblast growth factor-induced directional migration and tubular morphogenesis of microvascular endothelial cells. Accordingly, the peptide induced the loss of focal adhesions and actin stress fibers in these cells. Substitution of the arginine residues with alanines resulted in the loss of these properties. In the current study we describe a putative integrin-binding sequence with anti-migratory activity within endostatin.

Received for publication, November 26, 2003 , and in revised form, February 12, 2004.

^* This work was supported by the Academy of Finland, Sigrid Juselius Foundation, Biocentrum Helsinki, Helsinki University Hospital Fund, Novo Nordisk Foundation, Finnish Cancer Foundation, Finnish Medical Foundation, Emil Aaltonen Foundation, Ida Montin Foundation, Biomedicum Helsinki Foundation, and the University of Helsinki. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Laboratory of Cell Biology, Biomedicum Helsinki, POB 63 (Haartmaninkatu 8), FIN-00014, University of Helsinki, Finland. Tel.: 358-9-191-25566; Fax: 358-9-191-25573; E-mail: jorma.keski-oja{at}helsinki.fi.

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