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© The Rockefeller University Press,
0021-9525/2001//1087 $5.00
The Journal of Cell Biology, Volume 152, Number 5,
, 2001 1087-1098
Original Article |
Mammalian Sprouty-1 and -2 Are Membrane-Anchored Phosphoprotein Inhibitors of Growth Factor Signaling in Endothelial Cells
christofori{at}nt.imp.univie.ac.at
Growth factor–induced signaling by receptor tyrosine kinases (RTKs) plays a central role in embryonic development and in pathogenesis and, hence, is tightly controlled by several regulatory proteins. Recently, Sprouty, an inhibitor of Drosophila development-associated RTK signaling, has been discovered. Subsequently, four mammalian Sprouty homologues (Spry-1–4) have been identified. Here, we report the functional characterization of two of them, Spry-1 and -2, in endothelial cells. Overexpressed Spry-1 and -2 inhibit fibroblast growth factor– and vascular endothelial growth factor–induced proliferation and differentiation by repressing pathways leading to p42/44 mitogen-activating protein (MAP) kinase activation. In contrast, although epidermal growth factor–induced proliferation of endothelial cells was also inhibited by Spry-1 and -2, activation of p42/44 MAP kinase was not affected. Biochemical and immunofluorescence analysis of endogenous and overexpressed Spry-1 and -2 reveal that both Spry-1 and -2 are anchored to membranes by palmitoylation and associate with caveolin-1 in perinuclear and vesicular structures. They are phosphorylated on serine residues and, upon growth factor stimulation, a subset is recruited to the leading edge of the plasma membrane. The data indicate that mammalian Spry-1 and -2 are membrane-anchored proteins that negatively regulate angiogenesis-associated RTK signaling, possibly in a RTK-specific fashion.
Key Words: angiogenesis • endothelial cells • fibroblast growth factors • signal transduction • vascular endothelial growth factor
© 2001 The Rockefeller University Press
Abbreviations used in this paper: BCE, bovine capillary endothelial cell; DSpry, Drosophila Sprouty; EGF, epidermal growth factor; FGF, fibroblast growth factor; hSpry, human Sprouty; HUVEC, human umbilical vein endothelial cell; LDH, lactate dehydrogenase; MAP, mitogen-activating protein; MEK, MAP kinase kinase; mSpry, mouse Sprouty; PPC, particles per cell; RTK, receptor tyrosine kinase; VEGF, vascular EGF.
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