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Papers In Press, published online ahead of print May 19, 2006
Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
Corresponding Author: dthurmon{at}iupui.edu
The cycling of the small Rho family GTPase Cdc42 is required for insulin granule exocytosis, although the regulatory proteins involved in Cdc42 cycling in pancreatic beta-cells are unknown. Here we demonstrate that the caveolar protein Caveolin-1 (Cav-1) is a Cdc42 binding protein in beta-cells. Cav-1 associated with Cdc42-VAMP2-bound granules present near the plasma membrane under basal conditions. However, stimulation with glucose induced the dissociation of Cav-1 from Cdc42-VAMP2 complexes, coordinate with the timing of Cdc42 activation. Analyses of the Cav-1 scaffolding domain revealed a motif conserved in Rho family guanine nucleotide dissociation inhibitors (GDI), which suggested a novel role for Cav-1 as a Cdc42 GDI in beta-cells. The novel role was further supported by: 1) in vitro binding analyses that demonstrated a direct interaction between Cav-1 and Cdc42; 2) GST-Cdc42 interaction assays showing preferential Cav-1 binding to GDP-Cdc42 over that of GTP-Cdc42; 3) Cav-1 depletion studies resulting in an inappropriate 40% induction of activated Cdc42 in the absence of stimuli and also a 40% increase in basal insulin release from both MIN6 cells and islets. Expression of wild-type Cav-1 in Cav-1-depleted cells restored basal level secretion to normal, whereas expression of a scaffolding-domain mutant of Cav-1 failed to normalize secretion. Taken together, these data suggest that Cav-1 functions as a Cdc42 GDI in beta-cells, maintaining Cdc42 in an inactive state and regulating basal secretion in the absence of stimuli. Through its interaction with the Cdc42-VAMP2 bound insulin granule complex, Cav-1 may contribute to the specific targeting of granules to ‘active sites’ of exocytosis organized by caveolae..
J. Biol. Chem, 10.1074/jbc.M603604200
Submitted on April 13, 2006
Revised on May 16, 2006
Accepted on May 19, 2006
Caveolin-1 functions as a novel CDC42 guanine nucleotide dissociation inhibitor (GDI) in pancreatic beta cells
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