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Journal of Cellular Biochemistry

Fibroblast growth factor receptor-1 mediates the inhibition of endothelial cell proliferation and the promotion of skeletal myoblast differentiation by SPARC: A role for protein kinase A

Authors

  • Kouros Motamed,

    Corresponding author
    1. Department of Vascular Biology, The Hope Heart Institute, Seattle, Washington 98104-2046
    2. Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912-2500
    • Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd., CB-3207, Augusta, GA 30912-2500.
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  • David J. Blake,

    1. Department of Vascular Biology, The Hope Heart Institute, Seattle, Washington 98104-2046
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  • John C. Angello,

    1. Department of Biochemistry, University of Washington School of Medicine, Seattle, Washington 98195
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  • Benjamin L. Allen,

    1. Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706
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  • Alan C. Rapraeger,

    1. Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706
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  • Stephen D. Hauschka,

    1. Department of Biochemistry, University of Washington School of Medicine, Seattle, Washington 98195
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  • E. Helene Sage

    1. Department of Vascular Biology, The Hope Heart Institute, Seattle, Washington 98104-2046
    2. Department Biological Structure, University of Washington School of Medicine, Seattle, Washington 98195
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Abstract

The role of the matricellular protein SPARC (secreted protein, acidic and rich in cysteine) in modulation of vascular cell proliferation is believed to be mediated, in part, by its ability to regulate the activity of certain growth factors through direct binding. In this study, we demonstrate that SPARC does not bind to basic fibroblast growth factor (bFGF/FGF-2) or interfere with complex formation between FGF-2 and its high-affinity FGF receptor-1 (FGFR1), yet both native SPARC and a peptide derived from the C-terminal high-affinity Ca2+-binding region of protein significantly inhibit ligand-induced autophosphorylation of FGFR1 (>80%), activation of mitogen-activated protein kinases (MAPKs) (>75%), and DNA synthesis in human microvascular endothelial cells (HMVEC) stimulated by FGF-2 (>80%). We also report that in the presence of FGF-2, a factor which otherwise stimulates myoblast proliferation and the repression of terminal differentiation, both native SPARC and the Ca2+-binding SPARC peptide significantly promote (>60%) the differentiation of the MM14 murine myoblast cell line that expresses FGFR1 almost exclusively. Moreover, using heparan sulfate proteoglycan (HSPG)-deficient myeloid cells and porcine aortic endothelial cells (PAECs) expressing chimeric FGFR1, we show that antagonism of FGFR1-mediated DNA synthesis and MAPK activation by SPARC does not require the presence of cell-surface, low-affinity FGF-2 receptors, but can be mediated by an intracellular mechanism that is independent of an interaction with the extracellular ligand-binding domain of FGFR1. We also report that the inhibitory effect of SPARC on DNA synthesis and MAPK activation in endothelial cells is mediated in part (>50%) by activation of protein kinase A (PKA), a known regulator of Raf-MAPK pathway. SPARC thus modulates the mitogenic effect of FGF-2 downstream from FGFR1 by selective regulation of the MAPK signaling cascade. J. Cell. Biochem. 90: 408–423, 2003. © 2003 Wiley-Liss, Inc.

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