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J. Biol. Chem., Vol. 281, Issue 39, 29201-2912, September 29, 2006

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A Functional Interaction between Sprouty Proteins and Caveolin-1^*

From the Institute of Biochemistry and Genetics, Department of Clinical-Biological Sciences, Center of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland

Growth factor-mediated signal transduction cascades can be regulated spatio-temporally by signaling modulators, such as Sprouty proteins. The four mammalian Sprouty family members are palmitoylated phosphoproteins that can attenuate or potentiate numerous growth factor-induced signaling pathways. Previously, we have shown that Sprouty-1 and Sprouty-2 associate with Caveolin-1, the major structural protein of caveolae. Like Sprouty, Caveolin-1 inhibits growth factor-induced mitogen-activated protein kinase activation. Here, we demonstrate that all four mammalian Sprouty family members physically interact with Caveolin-1. The C terminus of Caveolin-1 is the major Sprouty-binding site, whereas Sprouty binds Caveolin-1 via its conserved C-terminal domain. A single point mutation in this domain results in loss of Caveolin-1 interaction. Moreover, we demonstrate that the various Sprouty isoforms differ dramatically in their cooperation with Caveolin-1-mediated inhibition of mitogen-activated protein kinase activation and that such cooperation is also highly dependent on the type of growth factor investigated and on cell density. Together, the data suggest that the Sprouty/Caveolin-1 interaction modulates signaling in a growth factor- and Sprouty isoform-specific manner.

Received for publication, April 24, 2006

^* This work was supported by a Swiss National Science Foundation grant (to G. C.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

³ The abbreviations used are: RTK, receptor tyrosine kinase; Spry, Sprouty; Cav-1, Caveolin-1; aa, amino acids; ERK, extracellular-regulated kinase; m, mouse; h, human; Ad, adenovirus; EGFP, enhanced green fluorescent protein; VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; EGF, epidermal growth factor; HEK, human embryonic kidney; TBST, Tris-buffered saline with 0.05% Tween 20; GST, glutathione S-transferase; HA, hemagglutinin; PBS, phosphate-buffered saline.

² To whom correspondence should be addressed. Tel.: 41-0-61-267-3561; Fax: 41-0-61-267-3566; E-mail: gerhard.christofori{at}unibas.ch.

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