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J. Biol. Chem. 276 (6): 4128-4133

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Inhibition of Angiogenesis by a Mouse Sprouty Protein*

Sang Hoon LeeDagger , Derrick J. SchlossDagger , Lesley Jarvis§, Mark A. Krasnow§, and Judith L. SwainDagger

From the Dagger  Department of Medicine, § Howard Hughes Medical Institute, Department of Biochemistry, Stanford University School of Medicine, S-102, Stanford, California 94305-5109

Sprouty negatively modulates branching morphogenesis in the Drosophila tracheal system. To address the role of mammalian Sprouty homologues in angiogenesis, another form of branching morphogenesis, a recombinant adenovirus engineered to express murine Sprouty-4 selectively in endothelial cells, was injected into the sinus venosus of embryonic day 9.0 cultured mouse embryos. Sprouty-4 expression inhibited branching and sprouting of small vessels, resulting in abnormal embryonic development. In vitro, Sprouty-4 inhibited fibroblast growth factor and vascular endothelial cell growth factor-mediated cell proliferation and migration and prevented basic fibroblast growth factor and vascular endothelial cell growth factor-induced MAPK phosphorylation in endothelial cells, indicating inhibition of tyrosine kinase-mediated signaling pathways. The ability of constitutively activated mutant RasL61 to rescue Sprouty-4 inhibition of MAPK phosphorylation suggests that Sprouty inhibits receptor tyrosine kinase signaling upstream of Ras. Thus, Sprouty may regulate angiogenesis in normal and disease processes by modulating signaling by endothelial tyrosine kinases.

* This work was supported by National Institutes of Health (NIH) Grants HL 26831 (to J. L. S.) and T32 HL07708 (to S. H. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The 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: Department of Medicine, Stanford University, S-102, 300 Pasteur Dr., Stanford, CA 94305-5109. Tel.: 650-489-7778; Fax: 650-725-8381; E-mail: jlswain@stanford.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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