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J. Biol. Chem., Vol. 283, Issue 42, 28329-28337, October 17, 2008

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Effect of FGF-binding Protein 3 on Vascular Permeability^*

From the Lombardi Cancer Center, Georgetown University, Washington, D. C. 20057

Fibroblast growth factor-binding protein 1 (FGF-BP1 is BP1) is involved in the regulation of embryonic development, tumor growth, and angiogenesis by mobilizing endogenous FGFs from their extracellular matrix storage. Here we describe a new member of the FGF-BP family, human BP3. We show that the hBP3 protein is secreted from cells, binds to FGF2 in vitro and in intact cells, and inhibits FGF2 binding to heparin. To determine the function of hBP3 in vivo, hBP3 was transiently expressed in chicken embryos and resulted in >50% lethality within 24 h because of vascular leakage. The onset of vascular permeability was monitored by recording the extravasation kinetics of FITC-labeled 40-kDa dextran microperfused into the vitelline vein of 3-day-old embryos. Vascular permeability increased as early as 8 h after expression of hBP3. The increased vascular permeability caused by hBP3 was prevented by treatment of embryos with PD173074, a selective FGFR kinase inhibitor. Interestingly, a C-terminal 66-amino acid fragment (C66) of hBP3, which contains the predicted FGF binding domain, still inhibited binding of FGF2 to heparin similar to full-length hBP3. However, expression of the C66 fragment did not increase vascular permeability on its own, but required the administration of exogenous FGF2 protein. We conclude that the FGF binding domain and the heparin binding domain are necessary for the hBP3 interaction with endogenous FGF and the activation of FGFR signaling in vivo.

Received for publication, March 18, 2008 , and in revised form, July 18, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 CA71508 (to A. W.) and P30 CA51008 from the NCI. 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.

¹ To whom correspondence should be addressed: Research Bldg. E311, Lombardi Cancer Center, Georgetown University, 3970 Reservoir Road, WA, DC 20057. Tel.: 202-687-3672; Fax: 202-687-4821; E-mail: wellstea{at}georgetown.edu.

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				K. A. Gibby, K. McDonnell, M. O. Schmidt, and A. Wellstein A distinct role for secreted fibroblast growth factor-binding proteins in development PNAS, May 26, 2009; 106(21): 8585 - 8590. [Abstract] [Full Text] [PDF]