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

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Abstract
Based on the finding that stimulation of the IGF‐II, receptor (IGF‐IIR) is capable of activating Gi2 and calcium channels in BALB/c 3T3 fibroblasts, it was found that purified IGF‐IIR can couple directly to purified Gi2 in phospholipid vesicles. IGF‐IIR–Gi2 coupling can be characterized as follows. IGF‐IIR directly couples to Gi2 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–Gi2 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 Gi2 among various G proteins. Finally, the activity of IGF‐IIR on Gi2 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 Gi2, and is located at residues 2410–2423 of the human receptor. Subsequent work has indicated that this region is responsible for Gi‐coupling function of intact IGF‐IIR. The most important extensions of this discovery are the following: (1) The structure–function relationship for the Gi‐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.

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