A Functional Interaction between Sprouty Proteins and Caveolin-1

Abstract

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.

Sprouty2-Mediated Inhibition of Fibroblast Growth Factor Signaling Is Modulated by the Protein Kinase DYRK1A

“…In addition, the analysis showed that both Spry2 and DYRK1A are present in the crude synaptosomal fraction, preferentially associated with the synaptic plasma membranes. Whereas Spry2 has been reported to localize to the plasma membrane through palmitoylation and/or caveolin binding (7,28), nothing about DYRK1A membrane association has been reported or inferred from its primary structure. DYRK1A distribution in VOL.…”

Intermolecular Interactions of Sprouty Proteins and Their Implications in Development and Disease

“…However, whether palmitoylation of Spry proteins is a dynamic process regulated by stimulation of cells with growth factors remains to be determined. Finally, Spry proteins may translocate to plasma membranes via interactions through their C-terminal regions with caveolin-1 after serine phosphorylation in response to growth factor stimulation (Impagnatiello et al, 2001;Cabrita et al, 2006). Whatever the mechanism, it is clear that translocation of Spry1 and Spry2 is necessary for inhibition of growth factor-stimulated cell migration, proliferation, and differentiation by Spry proteins (Yigzaw et al, 2001).…”

Sprouty2 expression controls endothelial monolayer integrity and quiescence

“…Kajita et al have shown that overexpression of SPRY2 inhibited PDGF-induced ERK1/2 activity in dense, but not in sparse NIH 3T3 fibroblast cell cultures [171]. In a similar fashion, SPRY2 function in T47D breast carcinoma cells also depended on cell density [157].…”

“…Several overexpressing studies [10,126,157] and SPRY2 knockout mice [151,[153][154][155] confirmed its potential as a negative regulator of several RTK-related signaling pathways. However, the endogenous expression pattern(s) of SPRY2 remain not well delineated, and it is unknown whether SPRY2 function regulates endothelial quiescence.…”

“…A few studies have shown density dependent effects of SPRY2 in fibroblasts and breast carcinoma cells [157,171,172]. However, a direct density-dependent regulation of SPRY2 has not been described.…”