The IGF-II receptor system: a G protein-linked mechanism.
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-G12 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.
Department of Medicine, Harvard Medical School, Charlestown, Massachusetts.
I
I
Nishimoto
D000595:Amino Acid Sequence; D000818:Animals; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000737:chemistry / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D011954:Receptors, Dopamine / Q000737:chemistry; D011976:Receptors, Muscarinic / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D017527:Receptor, IGF Type 2; D018341:Receptors, Adrenergic, alpha-2; D018343:Receptors, Adrenergic, beta-2; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D019204:GTP-Binding Proteins