Protein prenylation in glucose-induced insulin secretion from the pancreatic islet beta cell: a perspective

Abstract

Insulin secretion from the pancreatic beta-cell is regulated principally by the ambient concentration of glucose. However, the molecular and cellular mechanisms underlying the stimulus-secretion coupling of glucose-stimulated insulin secretion (GSIS) remain only partially understood. Emerging evidence from multiple laboratories suggests key regulatory roles for GTP-binding proteins (G-proteins) in the cascade of events leading to GSIS. This class of signaling proteins undergo a series of requisite post-translational modifications (e.g., prenylation) at their C-terminal cysteines, which appear to be necessary for their targeting to respective membranous sites for optimal interaction with their respective effector proteins. This communication represents a perspective on potential regulatory roles for protein prenylation steps (i.e., protein farnesylation and protein geranylgeranylation) in GSIS from the islet beta cell. Possible consequences of protein prenylation and potential mechanisms underlying glucose-induced regulation of prenylation, specifically in the context of GSIS are also discussed.

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Schematic representation of post-translational modification of small G-proteins or the γ subunit of trimeric G-proteins. The first step of this reaction sequence is incorporation of either a 15 (farnesyl group)- or a 20 (geranylger-anyl group)-carbon derivative of MVA into the C-terminal cysteine via a thioether linkage. This reaction is catalyzed by either FTase or GGTase, respectively.Following this, the three amino acids after the prenylated cysteine are removed by a protease, thereby exposing the carboxylate anion.This site is then methylated by a carboxyl methyl transferase, which transfers a methyl group onto the carboxylate group.These enzymes use S-adenosyl methionine as the methyl donor.We have demonstrated that glucose promotes the carboxyl methylation of specific proteins in insulin-secreting cells (e.g. Cdc42, Rap1 and γ subunits of trimeric GTPases; see text for additional details).FTase: farnesyl transferase; CMT: carboxyl methyl transferase and SAM: S-adenosyl methionine.