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Murine Epidermal Growth Factor (EGF) Fragment (33–42) Inhibits Both EGF- and Laminin-dependent Endothelial Cell Motility and Angiogenesis¹

Division of Biochemistry, School of Biology and Biochemistry, [J. N., W. N. S., B. W., N. V. M.] and Department of Anatomy, School of Biomedical Sciences [W. A., D. J. W.], The Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL and Department of Opthalmology, Royal Victoria Hospital, Belfast BT12 6BA [J. R. B.], Northern Ireland, United Kingdom

Laminin, murine epidermal growth factor (mEGF), and the synthetic laminin peptide Lam.B1_925–933 (a linear peptide from the B1 chain of murine laminin, CDPGYIGSR-amide) all stimulate endothelial cell motility above basal rates, whereas a synthetic mEGF fragment, mEGF_33–42 (a linear peptide from the C-loop of mEGF, acetyl-C-[S-Acm]-VIGYS-GDR-C-[S-Acm]-amide), inhibits motility. In both human SK HEP-1 and embryonic chick endothelial cells, mEGF_33–42 blocks both EGF- and laminin-stimulated locomotion of endothelial cells. In vivo, mEGF_33–42 also blocks both laminin- and mEGF-induced angiogenesis in the chick. In the human cell line, Lam.B1_925–933 has an additive effect in coincubation with either laminin or mEGF, but it blocks their effects in the chick cells. Lam.B1_925–933 alone stimulates angiogenesis in the chick but blocks laminin-induced angiogenesis. Thus, mEGF_33–42 acts as a general laminin antagonist, whereas Lam.B1_925–933 acts as a laminin agonist in human cells, but in chick cells it acts as a partial antagonist. We propose that the presence of an anionic group at the eighth residue of mEGF_33–42 may be the source of the antagonistic effects seen with this peptide as compared with the laminin fragment. These findings have important implications in the design of human antiangiogenic agents, and also in the use of chick models in the study of human disease.

¹ This study was supported by grants from the Association for International Cancer Research, Action Cancer (Northern Ireland), and the British Diabetic Association.

² To whom requests for reprints should be addressed.

Received 2/27/95. Accepted 6/27/95.

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