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Papers In Press, published online ahead of print November 9, 2004
Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
Corresponding Author: dthurmon{at}iupui.edu
In pancreatic beta cells, insulin granule exocytosis is regulated by SNARE [soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein (SNAP) receptor] proteins, and this is coupled to cortical F-actin reorganization via the Rho family GTPase Cdc42 by an unknown mechanism. We investigated interactions amongst the t-SNARE protein Syntaxin 1A and the v-SNARE protein VAMP2 with Cdc42 and compared these structural interactions with their functional importance to glucose-stimulated insulin secretion in MIN6 beta cells. Subcellular fractionation analyses revealed a parallel redistribution of Cdc42 and VAMP2 from the granule fraction to the plasma membrane in response to glucose, which temporally corresponded with the glucose-induced activation of Cdc42. Moreover, within these fractions Cdc42 and VAMP2 were found to co-immunoprecipitate under basal and glucose stimulated conditions, suggesting that they moved as a complex. Furthermore, VAMP2 bound both GST-Cdc42-GTPS and GST-Cdc42-GDP, indicating that the Cdc42-VAMP2 complex could form under both cytosolic GDP-bound Cdc42 and plasma membrane GTP-bound Cdc42 conformational conditions. In vitro binding analyses showed that VAMP2 bound directly to Cdc42, and that a heterotrimeric complex with Syntaxin 1A could also be formed. Deletion analyses of VAMP2 revealed that only the N-terminal 28 residues were required for Cdc42 binding. Expression of this 28-residue VAMP2 peptide in MIN6 beta cells resulted in the specific impairment of glucose-stimulated insulin secretion, indicating a functional importance for the Cdc42-VAMP2 interaction. Taken together, these data suggest a mechanism whereby glucose activates Cdc42 to induce the targeting of intracellular Cdc42-VAMP2-insulin granule complexes to Syntaxin 1A at the plasma membrane.
J. Biol. Chem, 10.1074/jbc.M409528200
Submitted on August 18, 2004
Revised on October 18, 2004
Accepted on November 9, 2004
A direct interaction between Cdc42 and VAMP2 regulates SNARE-dependent insulin exocytosis
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