The IGF‐II receptor system: A G protein‐linked mechanism

Abstract

Based on the finding that stimulation of the IGF‐II, receptor (IGF‐IIR) is capable of activating G_i2 and calcium channels in BALB/c 3T3 fibroblasts, it was found that purified IGF‐IIR can couple directly to purified G_i2 in phospholipid vesicles. IGF‐IIR–G_i2 coupling can be characterized as follows. IGF‐IIR directly couples to G_i2 in response to IGF‐II in a stoichiometrical manner, suggesting that IGF‐IIR works as a transmembrane signaling molecule and that the seven‐transmembrane structure is not essential for receptor‐G protein coupling. The mode of IGF‐IIR–G_i2 interaction is similar to that of conventional receptor–G protein coupling, suggesting that a common G protein recognition mechanism is shared by IGF‐IIR and conventional G‐coupled receptors. The action of IGF‐IIR is specific on G_i2 among various G proteins. Finally, the activity of IGF‐IIR on G_i2 is similarly potent across the species of the proteins. These characteristics led to the discovery of a 14‐amino‐acid region in IGF‐IIR that can directly interact with and activate G_i2, and is located at residues 2410–2423 of the human receptor. Subsequent work has indicated that this region is responsible for G_i‐coupling function of intact IGF‐IIR. The most important extensions of this discovery are the following: (1) The structure–function relationship for the G_i‐activating function of this 14‐amino‐acid sequence, (2) the prediction of G protein‐coupled functions of receptors based on the results obtained from 1), and (3) clarification of the detailed mechanism whereby ligand–receptor complex recognizes G proteins. This paper reviews what we have learned from IGF‐IIR in terms of receptor–G protein interfaces and discusses future prospects.